Substituted pyrazolo [1,5-A] pyrimidine compounds as TRK kinase inhibitors

ABSTRACT

Compounds of Formula I: 
                         
and salts thereof in which R 1 , R 2 , R 3 , R 4 , X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

The present invention relates to novel compounds, to pharmaceuticalcompositions comprising the compounds, to processes for making thecompounds and to the use of the compounds in therapy. More particularly,it relates to certain substituted pyrazolo[1,5-a]pyrimidine compoundswhich exhibit Trk family protein tyrosine kinase inhibition, and whichare useful in the treatment of pain, cancer, inflammation,neurodegenerative diseases and certain infectious diseases.

The current treatment regimes for pain conditions utilize severalclasses of compounds. The opioids (such as morphine) have severaldrawbacks including emetic, constipatory and negative respiratoryeffects, as well as the potential for addictions. Non-steroidalanti-inflammatory analgesics (NSAIDs, such as COX-1 or COX-2 types) alsohave drawbacks including insufficient efficacy in treating severe pain.In addition, COX-1 inhibitors can cause ulcers of the mucosa.Accordingly, there is a continuing need for new and more effectivetreatments for the relief of pain, especially chronic pain.

Trk's are the high affinity receptor tyrosine kinases activated by agroup of soluble growth factors called neurotrophins (NT). The Trkreceptor family has three members: TrkA, TrkB and TrkC. Among theneurotrophins are (i) nerve growth factor (NGF) which activates TrkA,(ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 which activateTrkB and (iii) NT3 which activates TrkC. Trk's are widely expressed inneuronal tissue and are implicated in the maintenance, signaling andsurvival of neuronal cells (Patapoutian, A. et al., Current Opinion inNeurobiology, 2001, 11, 272-280).

Inhibitors of the Trk/neurotrophin pathway have been demonstrated to beeffective in numerous pre-clinical animal models of pain. For example,antagonistic NGF and TrkA antibodies such as RN-624 have been shown tobe efficacious in inflammatory and neuropathic pain animal models(Woolf, C. J. et al. (1994) Neuroscience 62, 327-331; Zahn, P. K. et al.(2004) J. Pain 5, 157-163; McMahon, S. B. et al., (1995) Nat. Med. 1,774-780; Ma, Q. P. and Woolf, C. J. (1997) Neuroreport 8, 807-810;Shelton, D. L. et al. (2005) Pain 116, 8-16; Delafoy, L. et al. (2003)Pain 105, 489-497; Lamb, K. et al. (2003) Neurogastroenterol. Motil. 15,355-361; Jaggar, S. I. et al. (1999) Br. J. Anaesth. 83, 442-448) andneuropathic pain animal models (Ramer, M. S. and Bisby, M. A. (1999)Eur. J. Neurosci. 11, 837-846; Ro, L. S. et al. (1999); Pain 79, 265-274Herzberg, U. et al. (1997) Neuroreport 8, 1613-1618; Theodosiou, M. etal. (1999) Pain 81, 245-255; Li, L. et al. (2003) Mol. Cell. Neurosci.23, 232-250; Gwak, Y. S. et al. (2003) Neurosci. Lett. 336, 117-120).Additionally, recent literature indicates after inflammation, BDNFlevels and TrkB signaling is increased in the dorsal root ganglion (Cho,L. et al. Brain Research 1997, 749, 358) and several studies have showantibodies that decrease signaling through the BDNF/TrkB pathway inhibitneuronal hypersensitization and the associated pain (Chang-Qi, L et al.Molecular Pain 2008, 4:27).

It has also been shown that NGF secreted by tumor cells and tumorinvading macrophages directly stimulates TrkA located on peripheral painfibers. Using various tumor models in both mice and rats, it wasdemonstrated that neutralizing NGF with a monoclonal antibody inhibitscancer related pain to a degree similar or superior to the highesttolerated dose of morphine. In addition, activation of the BDNF/TrkBpathway has been implicated in numerous studies as a modulator ofvarious types of pain including inflammatory pain (Matayoshi, S., J.Physiol. 2005, 569:685-95), neuropathic pain (Thompson, S. W., Proc.Natl. Acad. Sci. USA 1999, 96:7714-18) and surgical pain (Li, C.-Q. etal., Molecular Pain, 2008, 4(28), 1-11). Because TrkA and TrkB kinasesmay serve as a mediator of NGF driven biological responses, inhibitorsof TrkA and/or other Trk kinases may provide an effective treatment forchronic pain states.

Recent literature has also shown that overexpression, activation,amplification and/or mutation of Trk kinases are associated with manycancers including neuroblastoma (Brodeur, G. M., Nat. Rev. Cancer 2003,3, 203-216), ovarian (Davidson. B., et al., Clin. Cancer Res. 2003, 9,2248-2259) and colorectal cancer (Bardelli, A., Science 2003, 300, 949).In preclinical models of cancer, non-selective small molecule inhibitorsof Trk A, B and C were efficacious in both inhibiting tumor growth andstopping tumor metastasis (Nakagawara, A. (2001) Cancer Letters169:107-114; Meyer, J. et al. (2007) Leukemia, 1-10; Pierottia, M. A.and Greco A., (2006) Cancer Letters 232:90-98; Eric Adriaenssens, E. etal. Cancer Res (2008) 68:(2) 346-351).

In addition, inhibition of the neurotrophin/Trk pathway has been shownto be effective in treatment of pre-clinical models of inflammatorydiseases with NGF antibodies or non-selective small molecule inhibitorsof Trk A, B and C. For example, inhibition of the neurotrophin/Trkpathway has been implicated in preclinical models of inflammatory lungdiseases including asthma (Freund-Michel, V; Frossard, N.; Pharmacology& Therapeutics (2008), 117(1), 52-76), interstitial cystitis (Hu VivianY; et. al. The Journal of Urology(2005), 173(3), 1016-21), inflammatorybowel diseases including ulcerative colitis and Crohn's disease (DiMola, F. F, et. al., Gut (2000), 46(5), 670-678) and inflammatory skindiseases such as atopic dermatitis (Dou, Y.-C.; et. al. Archives ofDermatological Research (2006), 298(1), 31-37), eczema and psoriasis(Raychaudhuri, S. P., et al., J. Investigative Dermatology (2004),122(3), 812-819).

The neurotrophin/Trk pathway, particularly BDNF/TrkB, has also beenimplicated in the etiology of neurodegenerative diseases includingmultiple sclerosis, Parkinson's disease and Alzheimer's Disease(Sohrabji, Farida; Lewis, Danielle K., Frontiers in Neuroendocrinology(2006), 27(4), 404-414).

The TrkA receptor is also thought to be critical to the disease processin the infection of the parasitic infection of Trypanosoma cruzi (Chagasdisease) in human hosts (de Melo-Jorge, M. et al. Cell Host & Microbe(2007), 1(4), 251-261).

Trk inhibitors may also find use in treating disease related to animbalance of the regulation of bone remodeling, such as osteoporosis,rheumatoid arthritis, and bone metastases. Bone metastases are afrequent complication of cancer, occurring in up to 70 percent ofpatients with advanced breast or prostate cancer and in approximately 15to 30 percent of patients with carcinoma of the lung, colon, stomach,bladder, uterus, rectum, thyroid, or kidney. Osteolytic metastases cancause severe pain, pathologic fractures, life-threatening hypercalcemia,spinal cord compression, and other nerve-compression syndromes. Forthese reasons, bone metastasis is a serious and costly complication ofcancer. Therefore, agents that can induce apoptosis of proliferatingosteoblasts would be highly advantageous. Expression of TrkA and TrkCreceptors has been observed in the bone forming area in mouse models ofbone fracture (K. Asaumi, et al., Bone (2000) 26(6) 625-633). Inaddition, localization of NGF was observed in almost all bone formingcells (K. Asaumi, et al.). Recently, it was demonstrated that a pan-Trkinhibitor inhibits the tyrosine signaling activated by neurotrophinsbinding to all three of the Trk receptors in human hFOB osteoblasts (J.Pinski, et al., (2002) 62, 986-989). These data support the rationalefor the use of Trk inhibitors for the treatment of bone remodelingdiseases, such as bone metastases in cancer patients.

Several classes of small molecule inhibitors of Trk kinases said to beuseful for treating pain or cancer are known (Expert Opin. Ther. Patents(2009) 19(3), 305-319).

Pyrazolo[1,5-a]pyrimidine compounds are known. For example,International patent application publication WO 2004/089415 disclosescertain pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds having aphenyl, thienyl or furyl group in the 5-position which are said to be11-beta-hydroxysteroid dehydrogenase type 1 inhibitors useful incombination therapies.

European patent application publication No. EP 1948633A2 describes5-phenyl-7-hydroxy-substituted pyrazolo[1,5-a]pyrimidine-3-carboxamidecompounds as casein kinase II modulators for treating cancer.

PCT publication WO 2010/051549 describes pyrazolopyrimidine compoundshaving the general structure:

said to be inhibitors of Jak kinases.

It has now been found that certain pyrazolo[1,5-a]pyrimidine compoundsbearing an aryl-substituted or heteroaryl-substituted heterocyclic groupat the 5-position and a group having the formula C(═O)NR¹R² at the3-position, wherein R¹ and R² are as defined herein, are inhibitors ofTrk kinases, in particular inhibitors of TrkA and/or TrkB and/or TrkC,and are useful for treating disorders and diseases such as cancer andpain, including chronic and acute pain. Certain compounds which areinhibitors of TrkA and/or TrkB may be useful in the treatment ofmultiple types of pain including inflammatory pain, neuropathic pain,and pain associated with cancer, surgery, and bone fracture. Inaddition, compounds of the invention may be useful for treating cancer,inflammation, neurodegenerative diseases and certain infectiousdiseases.

In addition, compounds of the invention have been shown to be selectivefor the Trk family of kinases over closely related kinases. Inparticular, compounds of the invention are more selective for inhibitingTrkA kinase activity over inhibiting the activity of one or more membersof the Jak kinase family (Jak1, Jak2, Jak3 and Tyk2) Inhibition of theJak family of kinases has been postulated or demonstrated to result inseveral unwanted side effects including CD8 T and NK cell depletion(which can result in loss of tumor surveillance and increasedinfections), elevated cholesterol, neutropenia, thrombocytopenia,decreased reticulocytes (resulting in anemia) and bone marrowsuppression (Igaz P. et al., Inflamm. Res., 2001, 50:435-441; O'Shea J.J., Immunity, 1997, 7:1-11; Ihle J. N. et al., Canc. J. Sci. Am., 1998,4 suppl 1 S84-91; Gupta P. et al., J. Clin. Pharm. 2009; Kremer J. M. etal., Arth. & Rheum., 2009, 60:1895-1905 and van Gurp E., et al., Am. J.Transpl, 2008, 8:1711-18). Accordingly, compounds of the invention maybe more suitable as therapeutic treatments owing to their ability toinhibit the Trk family of kinases in preference over closely relatedkinases such as the Jak family of kinases, and therefore may avoidunwanted side effects in a mammal being treated with a compound of theinvention.

Accordingly, one embodiment of this invention provides a compound of thegeneral Formula I:

or a salt thereof, wherein:

R¹ is H or (1-6C alkyl);

R² is H, (1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)difluoroalkyl,-(1-6C)trifluoroalkyl, -(1-6C)chloroalkyl, -(2-6C)chlorofluoroalkyl,-(2-6C)difluorochloroalkyl,-(2-6C)chlorohydroxyalkyl,-(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6Calkyl)SO₂NH₂, -(1-6C alkyl)NHSO₂(1-3C alkyl), -(1-6C alkyl)NH₂, -(1-6Calkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl)₂, -(1-6Calkyl)NHC(═O)O(1-4C alkyl), -(1-6C alkyl)hetCyc¹, -(1-6C alkyl)hetAr¹,hetAr², hetCyc², —O(1-6C alkyl) which is optionally substituted withhalogen, OH or (1-4C)alkoxy, —O(3-6C cycloalkyl), Cyc¹, -(1-6Calkyl)(3-6C cycloalkyl), -(1-6Calkyl)(1-4C alkoxy), -(1-6Chydroxyalkyl)(1-4C alkoxy), a bridged 7-membered cycloalkyl ringoptionally substituted with (1-6C)hydroxyalkyl, or a bridged 7-8membered heterocyclic ring having 1-2 ring nitrogen atoms;

or NR¹R² forms a 4-6 membered azacyclic ring optionally substituted withone or more substituents independently selected from (1-6C)alkyl, OH,CO₂H, (1-3C alkyl)CO₂H, —O(1-6C alkyl) and (1-6C)hydroxyalkyl;

hetCyc¹ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, wherein hetCyc¹ is optionallysubstituted with oxo, OH, halogen or (1-6C)alkyl;

hetCyc² is a 6 membered carbon-linked heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein hetCyc² isoptionally substituted with F, SO₂NH₂, SO₂(1-3C alkyl) or halogen;

hetAr¹ is a 5-membered heteroaryl ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with(1-4C)alkyl;

hetAr² is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atomsand optionally substituted with one or more substituents independentlyselected from (1-4C)alkyl, (3-6C)cycloalkyl, halogen and OH;

Cyc¹ is a 3-6 membered cycloalkyl ring which is optionally substitutedwith one or more substituents independently selected from -(1-4C alkyl),—OH, —OMe, —CO₂H, -(1-4C alkyl)OH, halogen and CF₃;

Y is (i) phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-4C)alkoxy, —CF₃—CHF₂, —O(1-4Calkyl)hetCyc³, -(1-4C alkyl)hetCyc³, —O(1-4C alkyl)O(1-3C alkyl) and—O(3-6C dihydroxyalkyl), or (ii) a 5-6 membered heteroaryl ring having aring heteroatom selected from N and S, wherein said heteroaryl ring isoptionally substituted with one or more substituents independentlyselected from halogen, —O(1-4C alkyl), (1-4C)alkyl and NH₂, or (iii) apyrid-2-on-3-yl ring optionally substituted with one or moresubstituents independently selected from halogen and (1-4C)alkyl;

hetCyc³ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with(1-6C)alkyl;

X is null, —CH₂—, —CH₂CH₂—, —CH₂O— or —CH₂NR^(d)—;

R^(d) is H or -(1-4C alkyl);

R³ is H or -(1-4C alkyl);

each R⁴ is independently selected from halogen, -(1-4C)alkyl, —OH,-(1-4C)alkoxy, —NH₂, —NH(1-4C alkyl) and —CH₂OH; and

n is 0, 1, 2, 3, 4, 5 or 6.

In one embodiment of Formula I, X is selected from any of the valuesdescribed above, other than null.

In one embodiment of Formula I, X is CH₂.

Compounds of Formula I include compounds of the general Formula Ia:

or a salt thereof, wherein:

R¹ is H or (1-6C alkyl);

R² is H, (1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl,-(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl) SO₂NH₂, -(1-6Calkyl)NHSO₂(1-3C alkyl), -(1-6C alkyl)NH₂, -(1-6C alkyl)NH(1-4C alkyl),-(1-6C alkyl)N(1-4C alkyl)₂, -(1-6C alkyl)hetCyc¹, -(1-6C alkyl)hetAr¹,hetAr², hetCyc², —O(1-6C alkyl), —O(3-6C cycloalkyl), Cyc¹, or a bridged7-membered cycloalkyl ring,

or NR¹R² forms a 4-6 membered azacyclic ring optionally substituted withone or more substituents independently selected from (1-6C)alkyl, OH,CO₂H and (1-3C alkyl)CO₂H;

hetCyc¹ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, wherein hetCyc¹ is optionallysubstituted with oxo;

hetCyc² is a 6 membered carbon-linked heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein hetCyc² isoptionally substituted with F, SO₂NH₂, or SO₂(1-3C alkyl);

hetAr¹ is a 5-membered heteroaryl ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with(1-4C)alkyl;

hetAr² is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atomsand optionally substituted with one or more substituents independentlyselected from (1-4C)alkyl;

Cyc¹ is a 3-6 membered cycloalkyl ring which is optionally substitutedwith one or more substituents independently selected from -(1-4C alkyl),—OH, —OMe, —CO₂H and -(1-4C alkyl)OH;

Y is (i) phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-4C)alkoxy, —CF₃—CHF₂, —O(1-4Calkyl)hetCyc³ and —O(1-4C alkyl)O(1-3C alkyl), or (ii) a 5-6 memberedheteroaryl ring having a ring heteroatom selected from N and S, whereinsaid heteroaryl ring is optionally substituted with one or moresubstituents independently selected from halogen, —O(1-4C alkyl) and(1-4C)alkyl;

hetCyc³ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O;

X is null, —CH₂—, —CH₂CH₂—, —CH₂O— or —CH₂NR^(d)—;

R^(d) is H or -(1-4C alkyl);

R³ is H or -(1-4C alkyl);

each R⁴ is independently selected from halogen, -(1-4C)alkyl, —OH,-(1-4C)alkoxy, —NH₂, —NH(1-4C alkyl) and —CH₂OH; and

n is 0, 1, 2, 3, 4, 5 or 6.

In one embodiment of Formula Ia, X is selected from any of the valuesdescribed above, other than null.

In one embodiment of Formula Ia, X is CH₂.

In certain embodiments of Formula I, R¹ is hydrogen.

In certain embodiments of Formula I, R¹ is -(1-6C)alkyl. Examplesinclude methyl, ethyl, propyl and isopropyl. A particular example ismethyl.

In certain embodiments of Formula I, R² is H or -(1-6C)alkyl.

In certain embodiments, R² is hydrogen. In one embodiment, R² and R¹ areboth hydrogen. In one embodiment, R² is hydrogen and R¹ is -(1-6Calkyl).

In certain embodiments, R² is selected from -(1-6C)alkyl,-(1-6C)fluoroalkyl, -(1-6C)difluoroalkyl, -(1-6C)trifluoroalkyl,-(1-6C)chloro alkyl, -(2-6C)chlorofluoroalkyl,-(2-6C)chlorohydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO₂NH₂, and-(1-6C alkyl)NHSO₂(1-3C alkyl).

In certain embodiments, R² is -(1-6C)alkyl. In certain embodiments R² isselected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl andtert-butyl. Particular examples include methyl, ethyl, isopropyl andtert-butyl. In one embodiment, R² is -(1-6C)alkyl and R¹ is hydrogen. Inone embodiment, R² is -(1-6C)alkyl and R¹ is (1-6C alkyl).

In certain embodiments, R² is selected from -(1-6C)fluoroalkyl,-(1-6C)difluoroalkyl, -(1-6C)trifluoroalkyl, -(1-6C)chloroalkyl,-(2-6C)chlorofluoroalkyl, -(2-6C)chlorohydroxyalkyl, -(1-6C alkyl)CN,-(1-6C alkyl)SO₂NH₂, and -(1-6C alkyl)NHSO₂(1-3C alkyl).

In certain embodiments, R² is selected from -(1-6C)fluoroalkyl, -(1-6Calkyl)CN, -(1-6C alkyl)SO₂NH₂, and -(1-6C alkyl)NHSO₂(1-3C alkyl).

In certain embodiments, R² is -(1-6C)fluoroalkyl. A particular exampleis —C(CH₃)₂CH₂F. In one embodiment, R² is -(1-6C)fluoroalkyl and R¹ ishydrogen. In one embodiment, R² is -(1-6C)fluoroalkyl and R¹ is (1-6Calkyl).

In certain embodiments, R² is -(1-6C)difluoroalkyl. Examples include—CHF₂ and —CH₂CHF₂. In one embodiment, R² is -(1-6C)difluoroalkyl and R¹is hydrogen. In one embodiment, R² is -(1-6C)difluoroalkyl and R¹ is(1-6C alkyl).

In certain embodiments, R² is -(1-6C)trifluoroalkyl. Examples includeCF₃, CH₂CF₃ and CH(CH₃)CF₃. In one embodiment, R² is-(1-6C)trifluoroalkyl and R¹ is hydrogen. In one embodiment, R² is-(1-6C)trifluoroalkyl and R¹ is (1-6C alkyl).

In certain embodiments, R² is -(1-6C)chloroalkyl. An example includesCH₂CH₂Cl. In one embodiment, R² is -(1-6C)chloroalkyl and R¹ ishydrogen. In one embodiment, R² is -(1-6C)chloroalkyl and R¹ is (1-6Calkyl).

In certain embodiments, R² is -(1-6C)chlorofluoroalkyl. An exampleincludes CH₂CHFCH₂Cl. In one embodiment, R² is -(1-6C)chlorofluoroalkyland R¹ is hydrogen. In one embodiment, R² is -(1-6C)chlorofluoroalkyland R¹ is (1-6C alkyl).

In certain embodiments, R² is -(1-6C)difluorochloroalkyl. An exampleincludes —CH₂CF₂CH₂Cl. In one embodiment, R² is-(1-6C)difluorochloroalkyl and R¹ is H. In one embodiment, R² is-(1-6C)difluorochloroalkyl and R¹ is (1-6C alkyl).

In certain embodiments, R² is -(2-6C)chlorohydroxyalkyl. An exampleincludes —CH₂CH(OH)CH₂Cl. In one embodiment, R² is-(2-6C)chlorohydroxyalkyl and R¹ is hydrogen. In one embodiment, R² is-(2-6C)chlorohydroxyalkyl and R¹ is (1-6C alkyl).

In certain embodiments, R² is selected from methyl, ethyl, propyl,isopropyl, isobutyl, tert-butyl, —C(CH₃)₂CH₂F, —CHF₂, —CH₂CHF₂, CF₃,CH₂CF₃, CH(CH₃)CF₃, CH₂CH₂Cl, CH₂CHFCH₂Cl, and —CH₂CF₂CH₂Cl.

In certain embodiments, R² is selected from methyl, ethyl, propyl,isopropyl, —CF₃ and —CH₂CF₃.

In certain embodiments, R² is -(1-6C)hydroxyalkyl or-(2-6C)dihydroxyalkyl.

In certain embodiments, R² is -(1-6C)hydroxyalkyl. Examples include—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, —CH₂CH(OH)CH₃, —C(CH₃)₂CH₂OH,—CH₂C(CH₃)₂OH, —CH(CH₃)CH₂OH, —CH₂C(CH₃)₂CH₂OH, —CH(CH₂OH)CH(CH₃)₂,—CH(CH₂CH₃)CH₂OH, and —CH(CH₂OH)C(CH₃)₃. A particular example is—CH₂CH₂OH. In one embodiment, R² is -(1-6C)hydroxyalkyl and R¹ ishydrogen. In one embodiment, R² is -(1-6C)hydroxyalkyl and R¹ is -(1-6Calkyl).

In certain embodiments, R² is -(2-6C)dihydroxyalkyl. Examples include—CH₂CH(OH)CH₂OH, —C(CH₃)(CH₂OH)₂, —CH(CH₂OH)₂ and —CH(CH₂OH)(CHOHCH₃).Particular examples include —CH₂CH(OH)CH₂OH and —C(CH₃)(CH₂OH)₂. In oneembodiment, R² is -(2-6C)dihydroxyalkyl and R¹ is hydrogen. In oneembodiment, R² is -(2-6C)dihydroxyalkyl and R¹ is -(1-6C alkyl).

In certain embodiments, R² is -(1-6C alkyl)CN. Particular examplesinclude —CH₂CN and —C(CH₃)₂CN. In one embodiment, R² is -(1-6C alkyl)CNand R¹ is hydrogen. In one embodiment, R² is -(1-6C alkyl)CN and R¹ is(1-6C alkyl).

In certain embodiments, R² is -(1-6C alkyl)SO₂NH₂. A particular exampleis —CH₂CH₂SO₂NH₂. In one embodiment, R² is -(1-6C alkyl)SO₂NH₂ and R¹ ishydrogen. In one embodiment, R² is -(1-6C alkyl)SO₂NH₂ and R¹ is (1-6Calkyl).

In certain embodiments, R² is -(1-6C alkyl)NHSO₂(1-3C alkyl). Particularexamples include —CH₂CH₂NHSO₂CH₃ and —C(CH₃)₂CH₂NHSO₂CH₃. In oneembodiment, R² is -(1-6C alkyl)NHSO₂(1-3C alkyl) and R¹ is hydrogen. Inone embodiment, R² is -(1-6C alkyl)NHSO₂(1-3C alkyl) and R¹ is (1-6Calkyl).

In certain embodiments, R² is selected from -(1-6C alkyl)NH₂, -(1-6Calkyl)NH(1-4C alkyl) and -(1-6C alkyl)N(1-4C alkyl)₂.

In certain embodiments, R² is -(1-6C alkyl)NH₂. Examples include—CH₂C(CH₃)₂NH₂ and —CH₂CH₂CH₂NH₂. A particular example is—CH₂C(CH₃)₂NH₂. In one embodiment, R² is -(1-6C alkyl)NH₂ and R¹ ishydrogen. In one embodiment, R² is -(1-6C alkyl)NH₂ and R¹ is (1-6Calkyl).

In certain embodiments, R² is -(1-6C alkyl)NH(1-4C alkyl). Examplesinclude groups having the formula -(1-4C alkyl)NHCH₃. A particular valueis —C(CH₃)₂NHCH₃. In one embodiment, R² is -(1-6C alkyl)NH(1-4C alkyl)and R¹ is hydrogen. In one embodiment, R² is -(1-6C alkyl)NH(1-4C alkyl)and R¹ is (1-6C alkyl).

In certain embodiments, R² is -(1-6C alkyl)N(1-4C alkyl)₂. Examplesinclude groups having the formula -(1-4C alkyl)N(CH₃)₂. A particularvalue is (1-6C alkyl)NMe₂. In one embodiment, R² is -(1-6C alkyl)N(1-4Calkyl)₂ and R¹ is hydrogen. In one embodiment, R² is -(1-6C alkyl)N(1-4Calkyl)₂ and R¹ is (1-6C alkyl).

In certain embodiments, R² is -(1-6C alkyl)NHC(═O)O(1-4C alkyl). Anexample includes CH₂CH₂CH₂NHC(═O)OC(CH₃)₃. In one embodiment, R² is-(1-6C alkyl)NHC(═O)O(1-4C alkyl) and R¹ is hydrogen. In one embodiment,R² is -(1-6C alkyl)NHC(═O)O(1-4C alkyl) and R¹ is (1-6C alkyl).

In certain embodiments, R² is selected from -(1-6C alkyl)hetCyc¹ and-(1-6C alkyl)hetAr¹.

In certain embodiments, R² is -(1-6C alkyl)hetCyc¹. Examples of hetCyc¹rings include morpholinyl, piperidinyl, piperazinyl and imidazolidinyl,each of which is optionally substituted with a substituent selected fromoxo, OH, halogen, and (1-6C)alkyl. In certain embodiments hetCyc¹ ismorpholinyl, piperidinyl, piperazinyl or imidazolidin-2-one optionallysubstituted with OH, halogen or (1-6C)alkyl. Examples of the-(1-6C)alkyl portion include methylene, ethylene, dimethylethylene, andthe like.

Examples of R² when represented by -(1-6C alkyl)hetCyc¹ include thestructures:

In certain embodiments, R² when represented by -(1-6C alkyl)hetCyc¹includes the structures:

In certain embodiments hetCyc¹ is morpholinyl or imidazolidin-2-one.

In one embodiment, R² is -(1-6C alkyl)hetCyc¹ and R¹ is hydrogen. In oneembodiment, R² is -(1-6C alkyl)hetCyc¹ and R¹ is (1-6C alkyl).

In certain embodiments, R² is -(1-6C alkyl)hetAr¹. Examples of hetAr¹include furanyl, pyrazolyl, and imidazolyl rings which are optionallysubstituted with -(1-4C alkyl), for example methyl. Examples of the-(1-6C)alkyl portion include methylene, ethylene, dimethylmethylene, andthe like. Examples of R² when represented by -(1-6C alkyl)hetAr¹ includethe structures:

Particular values for R² when represented by -(1-6C alkyl)hetAr¹ includethe structures:

In one embodiment, R² is -(1-6C alkyl)hetAr¹ and R¹ is hydrogen. In oneembodiment, R² is -(1-6C alkyl)hetAr¹ and R¹ is (1-6C alkyl).

In certain embodiments, R² is hetAr². Examples of hetAr² includepyridyl, pyrazolyl and imidazolyl rings optionally substituted with oneor more substituents independently selected from (1-4C)alkyl,(3-6C)cycloalkyl, halogen and OH. Particular examples of hetAr²substituents include methyl, ethyl, isopropyl, cyclopropyl, fluoro andhydroxy. Particular examples of hetAr² include the structures:

In certain embodiments hetAr² is a pyridyl or pyrazolyl ring optionallysubstituted with one or more substituents independently selected from-(1-4C)alkyl, for example one or more methyl groups, for example 1 or 2methyl groups. Particular examples of hetAr² include the structures:

In one embodiment, R² is hetAr² and R¹ is hydrogen. In one embodiment,R² is hetAr² and R¹ is (1-6C alkyl).

In certain embodiments, R² is hetCyc². Examples of hetCyc² includepiperidinyl and tetrahydropyranyl rings optionally substituted with F,SO₂NH₂ or SO₂(1-3C alkyl). Particular examples of R² when represented byhetCyc² include the structures:

In one embodiment, R² is hetCyc² and R¹ is hydrogen. In one embodiment,R² is hetCyc² and R¹ is (1-6C alkyl).

In certain embodiments, R² is —O(1-6C alkyl) which is optionallysubstituted with halogen, OH or (1-4C)alkoxy. Examples include —OMe,—OEt, —OCH₂CH₂OC(CH₃)₃, —OCH₂CH₂Br, —OCH₂CH₂Cl and —OCH₂CH₂OH. In oneembodiment, R² is —O(1-6C alkyl) which is optionally substituted withhalogen, OH or (1-4C)alkoxy, and R¹ is hydrogen. In one embodiment, R²is —O(1-6C alkyl) which is optionally substituted with halogen, OH or(1-4C)alkoxy, and R¹ is (1-6C alkyl).

In certain embodiments, R² is —O(1-6C alkyl). Particular examplesinclude OMe and OEt.

In certain embodiments, R² is —O(3-6C cycloalkyl). A particular exampleis cyclopropoxy. In one embodiment, R² is —O(3-6C cycloalkyl) and R¹ ishydrogen. In one embodiment, R² is —O(3-6C cycloalkyl) and R¹ is (1-6Calkyl).

In certain embodiments, R² is —O(1-6C alkyl) or —O(3-6C cycloalkyl)

In certain embodiments, R² is Cyc¹ or a bridged 7-membered cycloalkylring.

In certain embodiments, R² is Cyc¹, wherein Cyc¹ is a 3-6 memberedcycloalkyl ring optionally substituted with one or more substituentsindependently selected from -(1-4C alkyl), —OH, —OMe, —CO₂H, -(1-4Calkyl)OH, halogen and CF₃. In one embodiment, Cyc¹ is optionallysubstituted with one or more substituents independently selected frommethyl, —OH, —OMe, —CO₂H, CH₂OH, CH₂CH₂OH and CF₃. In certainembodiments, R² is Cyc¹, wherein the cycloalkyl ring is optionallysubstituted with one or more substituents independently selected from-(1-4C alkyl), —OH, —OMe, —CO₂H and -(1-4C alkyl)OH, such as one or moresubstituents independently selected from methyl, —OH, —CH₂OH and —CO₂H.In one embodiment, Cyc¹ is optionally substituted with one or moresubstituents independently selected from methyl, —OH, —CH₂OH and —CO₂H.In one embodiment, Cyc¹ is optionally substituted with one or two ofsaid substituents.

Examples of R² when represented by Cyc¹ include the structures:

Particular examples of R² when represented by Cyc¹ include thestructures:

In one embodiment of Formula I, Cyc¹ is a 3, 4 or 5 membered cycloalkylring which is optionally substituted with one or more substituentsindependently selected from -(1-4C alkyl), —OH, —OMe, —CO₂H, -(1-4Calkyl)OH, halogen and CF₃.

In one embodiment of Formula I, Cyc¹ is a 3, 4 or 5 membered cycloalkylring which is optionally substituted with one or more substituentsindependently selected from -(1-4C alkyl), —OH, OMe, —CO₂H and -(1-4Calkyl)OH.

In one embodiment, R² is cyclopropyl.

In one embodiment R₂ is selected from the structures:

In one embodiment, R² is Cyc¹ and R¹ is hydrogen. In one embodiment, R²is Cyc¹ and R¹ is (1-6C alkyl).

In one embodiment, R² is a 3, 4 or 5 membered cycloalkyl ring which isoptionally substituted with one or more substituents independentlyselected from -(1-4C alkyl), —OH, —OMe, —CO₂H, -(1-4C alkyl)OH, halogenand CF₃.

In one embodiment, R² is a 3, 4 or 5 membered cycloalkyl ring which isoptionally substituted with one or more substituents independentlyselected from -(1-4C alkyl), —OH, OMe, —CO₂H and -(1-4C alkyl)OH.

In one embodiment, R² is a 3, 4 or 5 membered cycloalkyl ring which isoptionally substituted with one or more substituents independentlyselected from methyl, —CO₂H, and CH₂OH.

In certain embodiments, R² is cyclopropyl optionally substituted withone or more substituents independently selected from -(1-4C alkyl), —OH,—OMe, —CO₂H, -(1-4C alkyl)OH, halogen and CF₃.

In certain embodiments, R² is cyclopropyl optionally substituted withone or more substituents independently selected from methyl, —CO₂H, andCH₂OH.

In certain embodiments, R² is cyclobutyl optionally substituted with oneor more substituents independently selected from -(1-4C alkyl), —OH,—OMe, —CO₂H, -(1-4C alkyl)OH, halogen and CF₃. In certain embodiments,R² is cyclobutyl optionally substituted with one or more substituentsindependently selected from methyl, —OH, —OMe, —CO₂H, CH₂OH, CH₂CH₂OHand CF₃.

In certain embodiments, R² is cyclopentyl optionally substituted withone or more substituents independently selected from -(1-4C alkyl), —OH,—OMe, —CO₂H, -(1-4C alkyl)OH, halogen and CF₃. In certain embodiments,R² is cyclopentyl optionally substituted with one or more substituentsindependently selected from methyl, —OH, —OMe, —CO₂H, CH₂OH, CH₂CH₂OHand CF₃.

In certain embodiments, R² is cyclohexyl optionally substituted with oneor more substituents independently selected from -(1-4C alkyl), —OH,—OMe, —CO₂H, -(1-4C alkyl)OH, halogen and CF₃. In certain embodiments,R² is cyclohexyl optionally substituted with one or more substituentsindependently selected from methyl, —OH, —OMe, —CO₂H, CH₂OH, CH₂CH₂OHand CF₃.

In certain embodiments, R² is -(1-6C alkyl)(3-6C cycloalkyl). Examplesof the (1-6C alkyl) portion include methyl, ethyl, propyl and butyl.Examples of the cycloalkyl portion include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. In one embodiment, the cycloalkyl portion iscyclopropyl. Particular examples include the structures:

In one embodiment, R² is -(1-6C alkyl)(3-6C cycloalkyl) and R¹ ishydrogen. In one embodiment, R² is -(1-6C alkyl)(3-6C cycloalkyl) and R¹is (1-6C alkyl).

In certain embodiments, R² is -(1-6Calkyl)(1-4C alkoxy). Examplesinclude CH₂CH₂OCH₃ and CH(CH₃)CH₂OCH₃. In one embodiment, R² is-(1-6Calkyl)(1-4C alkoxy) and R¹ is hydrogen. In one embodiment, R² is-(1-6Calkyl)(1-4C alkoxy) and R¹ is (1-6C alkyl).

In certain embodiments, R² is -(1-6C hydroxyalkyl)(1-4C alkoxy). Anexample includes —CH₂CH(OH)CH₂OCH₃. In one embodiment, R² is -(1-6Chydroxyalkyl)(1-4C alkoxy) and R¹ is hydrogen. In one embodiment, R² is-(1-6C hydroxyalkyl)(1-4C alkoxy) and R¹ is (1-6C alkyl).

In certain embodiments, R² is a bridged 7-membered cycloalkyl ring. Incertain embodiments, R² is a bridged 7-membered cycloalkyl ringoptionally substituted with (1-6C)hydroxyalkyl. In certain embodiments,R² is a bridged 7-membered cycloalkyl ring optionally substituted withhydroxymethyl. Examples of R² include the structures:

A particular example or R² is the structure:

In one embodiment, R² is a bridged 7-membered cycloalkyl ring optionallysubstituted with (1-6C)hydroxyalkyl and R¹ is hydrogen. In oneembodiment, R² is a bridged 7-membered cycloalkyl ring and R¹ is (1-6Calkyl).

In certain embodiments, R² is a bridged 7-8 membered heterocyclic ringhaving 1-2 ring nitrogen atoms. A particular example is the structure:

In one embodiment, R² is a bridged 7-8 membered heterocyclic ring having1-2 ring nitrogen atoms and R¹ is hydrogen. In one embodiment, R² is abridged 7-8 membered heterocyclic ring having 1-2 ring nitrogen atomsand R¹ is (1-6C alkyl).

In certain embodiments, NR¹R² forms a 4-6 membered azacyclic ringoptionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, OH, CO₂H, (1-3C alkyl)CO₂H, —O(1-6C alkyl)and (1-6C)hydroxyalkyl. Examples include 4-6 membered azacyclic ringsoptionally substituted with one or more groups independently selectedfrom methyl, OH, —C(═O)OH, —CH₂COOH, OMe, and —CH₂OH. In certainembodiments, the azacyclic ring is optionally substituted with one ortwo of said substituents. Particular examples include the structures:

In certain embodiments, NR¹R² forms a 4-6 membered azacyclic ringoptionally substituted with one or more substituents independentlyselected from -(1-6C)alkyl, —OH, —CO₂H and -(1-3C alkyl)CO₂H. Examplesinclude 4-6 membered azacyclic rings optionally substituted with one ortwo groups independently selected from methyl, OH, —C(═O)OH and—CH₂COOH. Particular examples include the structures:

Compounds of Formula I also include compounds wherein:

R¹ is H or -(1-6C alkyl);

R² is H, -(1-6 C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl,-(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO₂NH₂, -(1-6Calkyl)NHSO₂(1-3C alkyl), -(1-6C alkyl)NH₂, -(1-6C alkyl)NH(1-4C alkyl),-(1-6C alkyl)N(1-4C alkyl)₂, -(1-6C alkyl)hetCyc¹, -(1-6C alkyl)hetAr¹,hetAr², —O(1-6C alkyl), —O(3-6C cycloalkyl), or a 3, 4 or 5 memberedcycloalkyl ring optionally substituted with one or more substituentsindependently selected from -(1-4C alkyl), —OH, OMe, —CO₂H and -(1-4Calkyl)OH;

or NR¹R² forms a 4-6 membered azacyclic ring optionally substituted withone or more substituents independently selected from -(1-6C)alkyl, —OH,—CO₂H and -(1-3C alkyl)CO₂H;

and X, Y, R³, R⁴ and n are as defined for Formula I.

Compounds of Formula I also include compounds wherein:

R¹ is H or -(1-6C alkyl);

R² is H, -(1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl,-(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO₂NH₂, -(1-6Calkyl)NHSO₂(1-3C alkyl), -(1-6C alkyl)NH₂, -(1-6C alkyl)NH(1-4C alkyl),-(1-6C alkyl)N(1-4C alkyl)₂, -(1-6C alkyl)hetCyc¹, -(1-6C alkyl)hetAr¹,hetAr², hetCyc², —O(1-6C alkyl), —O(3-6C cycloalkyl), or a bridged7-membered cycloalkyl ring,

or NR¹R² forms a 4-6 membered azacyclic ring optionally substituted withone or more substituents independently selected from -(1-6C)alkyl, —OH,—CO₂H and -(1-3C alkyl)CO₂H; and

and X, Y, R³, R⁴ and n are as defined for Formula I.

Referring now to the substituents on the ring at the 5-position ofFormula I, wherein the 5-position is identified in the followingstructure:

in one embodiment Y is phenyl optionally substituted with one or moresubstituents independently selected from halogen, (1-4C)alkoxy,—CF₃—CHF₂, —O(1-4C alkyl)hetCyc³, -(1-4C alkyl)hetCyc³, —O(1-4Calkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl).

In one embodiment, Y is phenyl optionally substituted with one or two ofsaid substituents. In one embodiment Y is phenyl optionally substitutedwith one or more substituents independently selected from halogen,(1-4C)alkoxy, —O(1-4C alkyl)hetCyc³, -(1-4C alkyl)hetCyc³, —O(1-4Calkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl). In one embodiment, Y isphenyl optionally substituted with one or two of said substituents.

In one embodiment, Y is phenyl optionally substituted with one or moresubstituents independently selected from —F, —Cl, —OMe, —CF₃, —CHF₂,morpholinylethoxy, morpholinylethyl, —OCH₂CH₂OMe, 2,3-dihydroxypropoxyand 2,2-dimethyl-1,3-dioxolanyl. In one embodiment, Y is phenyloptionally substituted with one or two of said substituents.

The term “morpholinylethoxy” as used herein refers to a morpholinyl ringsubstituted at the nitrogen ring atom with an ethoxy group and can berepresented by the structure:

The term “morpholinylethyl” as used herein refers to a morpholinyl ringsubstituted at the nitrogen ring atom with an ethyl group and can berepresented by the structure:

Example of Y include phenyl, 3-fluorophenyl, 2,5-difluorophenyl,2-chloro-5-fluorophenyl, 2-methoxyphenyl, 2-methoxy-5-fluorophenyl,2-trifluoromethyl-5-fluorophenyl, 2-difluoromethyl-5-fluorophenyl,3-chloro-5-fluorophenyl, 3-fluoro-5-(2-morpholinylethoxy)phenyl,3-fluoro-5-(2-morpholinylethyl)phenyl,5-fluoro-2-(2-morpholinylethyl)phenyl, 3-fluoro-5-methoxyethoxyphenyl,5-fluoro-2-methoxyethoxyphenyl,3-fluoro-5-(2,3-dihydroxypropoxyl)phenyl,2-(2,3-dihydroxypropoxy)-5-fluorophenyl,

The terms “3-fluoro-5-(2-morpholinylethoxyl)phenyl”,“3-fluoro-5-(2-morpholinylethyl)phenyl” and“5-fluoro-2-(2-morpholinylethyl)phenyl” can be represented by thestructures:

respectively.

In one embodiment, Y is fluorophenyl optionally substituted with asubstituent selected from —O(1-4C alkyl)hetCyc³, -(1-4C alkyl)hetCyc³,—O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl).

In one embodiment, Y is fluorophenyl substituted with a substituentselected from morpholinylethoxy, morpholinylethyl, —OCH₂CH₂OMe,2,3-dihydroxypropoxy and 2,2-dimethyl-1,3-dioxolanyl.

In one embodiment, Y is selected from3-fluoro-5-(2-morpholinylethoxyl)phenyl,5-fluoro-2-(2-morpholinoethoxyl)phenyl, 3-fluoro-5-methoxyethoxyphenyl,3-fluoro-5-(2-morpholinylethyl)phenyl,5-fluoro-2-(2-morpholinylethyl)phenyl,3-fluoro-5-(2,3-dihydroxypropoxyl)phenyl,2-(2,3-dihydroxypropoxy)-5-fluorophenyl,

In one embodiment Y is phenyl optionally substituted with one or moresubstituents independently selected from halogen, -(1-4C)alkoxy, —CF₃,—CHF₂, —O(1-4C alkyl)hetCyc³ and —O(1-4C alkyl)O(1-3C alkyl).

In one embodiment, Y is phenyl optionally substituted with one or moresubstituents independently selected from —F, —Cl, —OMe, —CF₃, —CHF₂,morpholinylethoxy and OCH₂CH₂OMe. In certain embodiments, Y is phenyloptionally substituted with one or two of said substituents. Particularvalues for Y include phenyl, 3-fluorophenyl, 2,5-difluorophenyl,2-chloro-5-fluorophenyl, 2-methoxyphenyl, 2-methoxy-5-fluorophenyl,2-trifluoromethyl-5-fluorophenyl, 2-difluoromethyl-5-fluorophenyl,3-chloro-5-fluorophenyl, 3-fluoro-5-(2-morpholinylethoxyl)phenyl,5-fluoro-2-(2-morpholinoethoxyl)phenyl, 3-fluoro-5-methoxyethoxyphenyland 5-fluoro-2-methoxyethoxyphenyl.

In one embodiment, Y is a 5-6 membered heteroaryl ring having a ringheteroatom selected from N and S, wherein said heteroaryl ring isoptionally substituted with one or more substituents independentlyselected from halogen, —O(1-4C alkyl), (1-4C)alkyl and NH₂. Examplesinclude pyridyl and thienyl groups optionally substituted with one ormore substituents independently selected from halogen, —O(1-4C alkyl),(1-4C)alkyl and NH₂.

In certain embodiments, Y is pyridyl optionally substituted with one ormore substituents independently selected from fluoro, chloro, methoxy,methyl, ethyl, and amino.

In certain embodiments Y is pyrid-2-yl, pyrid-3-yl, 5-fluoropyrid-3-yl,2-methoxy-5-fluoropyridy-3-yl, 2-chloro-5-fluoropyridy-3-yl,2-methyl-5-fluoropyrid-3-yl, 2-ethyl-5-fluoropyrid-3-yl or2-amino-5-fluoropyrid-3-yl.

In certain embodiments, Y is pyridyl substituted with one or moresubstituents independently selected from halogen, (1-4C)alkyl and amino.

In certain embodiments, Y is pyridyl substituted with one or moresubstituents independently selected from halogen and (1-4C)alkyl.

In certain embodiments, Y is pyridyl substituted with one or moresubstituents independently selected from fluoro, chloro, methyl andethyl.

In certain embodiments, Y is pyridyl substituted with one or moresubstituents independently selected from F, methyl and ethyl.

In certain embodiments, Y is 5-fluoropyrid-3-yl,2-methyl-5-fluoropyrid-3-yl or 2-ethyl-5-fluoropyrid-3-yl.

In certain embodiments, Y is 5-fluoropyrid-3-yl.

In one embodiment, Y is a 5-6 membered heteroaryl ring having a ringheteroatom selected from N and S, wherein said heteroaryl ring isoptionally substituted with one or more substituents independentlyselected from halogen, —O(1-4C alkyl) and (1-4C)alkyl. Examples includepyridyl and thienyl groups optionally substituted with one or moresubstituents independently selected from halogen, —O(1-4C alkyl) and(1-4C)alkyl, for example one or more substituents independently selectedfrom fluoro, methoxy and methyl. Particular values for Y includepyrid-2-yl, pyrid-3-yl, 5-fluoropyrid-3-yl,2-methoxy-5-fluoropyridy-3-yl and 2-methyl-5-fluoropyridy-3-yl.

In one embodiment, Y is a pyrid-2-on-3-yl ring optionally substitutedwith one or more substituents independently selected from halogen and(1-4C)alkyl. Examples include pyrid-2-on-3-yl rings optionallysubstituted with one or more substituents independently selected fromfluoro and methyl. In certain embodiments the pyrid-2-on-3-yl ring isoptionally substituted with one or two of said substituents. In oneembodiment, Y is 5-fluoropyridin-2(1H)-one optionally substituted with(1-4C)alkyl, for example methyl. Particular values for Y include thestructures:

In one embodiment, the Y group has the absolute configuration shown inFigure Ia:

wherein R¹, R², R³, R⁴, X, Y and n are as defined herein.

With reference to the R³ substituent, in one embodiment R³ is H.

In one embodiment, R³ is -(1-4C)alkyl, for example, methyl, ethyl,propyl, isopropyl or butyl. In one embodiment, R³ is methyl.

With reference to the R⁴ substituent, in one embodiment R⁴ is halogen.Particular examples are fluoro and chloro.

In one embodiment, R⁴ is -(1-4C)alkyl, such as methyl, ethyl, propyl,isopropyl, or butyl. A particular example is methyl.

In one embodiment, R⁴ is —OH.

In one embodiment, R⁴ is (1-4C)alkoxy, for example —OMe and —OEt.

In one embodiment, R⁴ is —NH₂.

In one embodiment, R⁴ is —NH(1-4C alkyl), for example —NHMe, —NHEt,—NHPr, —NHiPr or —NHBu. A particular example is —NHMe.

In one embodiment, R⁴ is CH₂OH.

In one embodiment, each R⁴ is independently selected from —F, —Cl, —OH,—OMe, —NH₂, —Me, —CH₂OH and —NHMe.

In one embodiment, n is 0, 1, 2, 3 or 4. In one embodiment, n is 0, 1, 2or 3. In one embodiment, n is 0, 1 or 2.

In one embodiment, n is 0.

In one embodiment, n is 1.

In one embodiment, n is 2.

With reference to the heterocyclic ring directly attached to the5-position of Formula I, in certain embodiments, X is null, —CH₂— orCH₂CH₂—.

In one embodiment X is null, such that the heterocyclic ring at the5-position of Formula I has the structure:

where R³, R⁴, Y and n are as defined herein. In one embodiment, Y isphenyl optionally substituted with one or more substituentsindependently selected from halogen, -(1-4C)alkoxy, —CF₃ and —CHF₂. Inone embodiment, Y is phenyl, 3-fluorophenyl and 2,5-difluorophenyl. Inone embodiment, Y is 5-6 membered heteroaryl ring having a ringheteroatom selected from N and S, wherein said heteroaryl ring isoptionally substituted with one or more substituents independentlyselected from halogen, —O(1-4C alkyl) and (1-4C)alkyl, for example oneor more halogen atoms. In one embodiment, Y is pyridyl. In oneembodiment, R³ is hydrogen. In another embodiment, R³ is methyl. In oneembodiment, n is 0. A particular example of the ring at the 5-positionof Formula I when X is null includes the structures:

In one embodiment, X is CH₂, such that the heterocyclic ring at the5-position of Formula I has the structure:

where R³, R⁴, Y and n are as defined herein. In one embodiment, X isCH₂, R³, R⁴ and n are as defined herein, and Y is phenyl optionallysubstituted with one or more substituents independently selected from—F, —Cl, —OMe, —CF₃, —CHF₂, morpholinylethoxy, morpholinylethyl,—OCH₂CH₂OMe, 2,3-dihydroxypropoxy and 2,2-dimethyl-1,3-dioxolanyl.

In one embodiment, X is CH₂, R³, R⁴ and n are as defined herein, and Yis phenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-chloro-5-fluorophenyl,2-methoxyphenyl, 2-methoxy-5-fluorophenyl,2-trifluoromethyl-5-fluorophenyl, 2-difluoromethyl-5-fluorophenyl,3-chloro-5-fluorophenyl, 3-fluoro-5-(2-morpholinylethoxy)phenyl,3-fluoro-5-(2-morpholinylethyl)phenyl,5-fluoro-2-(2-morpholinylethyl)phenyl, 3-fluoro-5-methoxyethoxyphenyl,5-fluoro-2-methoxyethoxyphenyl,3-fluoro-5-(2,3-dihydroxypropoxyl)phenyl,2-(2,3-dihydroxypropoxy)-5-fluorophenyl,

In one embodiment, X is CH₂, R³, R⁴ and n are as defined herein, and Yis fluorophenyl substituted with a substituent selected frommorpholinylethoxy, —OCH₂CH₂OMe, 2,3-dihydroxypropoxy and2,2-dimethyl-1,3-dioxolanyl.

In one embodiment, X is CH₂, Y and R⁴ are as defined herein, and R³ ishydrogen. In another embodiment, X is CH₂, Y and R⁴ are as definedherein, and R³ is methyl. In one embodiment, each R⁴ is independentlyselected from F, Cl, Me, OH, OMe, NH₂, NHMe, CH₂OH, CHF₂ and CF₃. In oneembodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is2.

In one embodiment X is CH₂, R³, R⁴ and n are as defined herein, and Y isa 5-6 membered heteroaryl ring having a ring heteroatom selected from Nand S, wherein said heteroaryl ring is optionally substituted with oneor more substituents independently selected from halogen, —O(1-4Calkyl), (1-4C)alkyl and NH₂.

In one embodiment, X is CH₂, R³, R⁴ and n are as defined herein, and Yis pyrid-2-yl, pyrid-3-yl, 5-fluoropyrid-3-yl,2-chloro-5-fluoropyridy-3-yl, 2-methyl-5-fluoropyrid-3-yl, or2-ethyl-5-fluoropyrid-3-yl. In one embodiment, R³ is hydrogen. Inanother embodiment, R³ is methyl. In one embodiment, each R⁴ isindependently selected from F, Cl, Me, OH, OMe, NH₂, NHMe, CH₂OH, CHF₂and CF₃. In one embodiment, n is 0. In one embodiment, n is 1. In oneembodiment, n is 2.

In one embodiment, X is CH₂, R³, R⁴ and n are as defined herein, and Yis pyridyl optionally substituted with one or more substituentsindependently selected from halogen and (1-4C)alkyl.

In one embodiment, X is CH₂, R³, R⁴ and n are as defined herein, and Yis pyridyl optionally substituted with one or more substituentsindependently selected from fluoro, methyl and ethyl.

In one embodiment, X is CH₂, R³, R⁴ and n are as defined herein, and Yis 5-fluoropyrid-3-yl, 2-methyl-5-fluoropyrid-3-yl, or2-ethyl-5-fluoropyrid-3-yl. In one embodiment, R³ is hydrogen.

In one embodiment, X is CH₂, R³, R⁴ and n are as defined herein, and Yis a pyrid-2-on-3-yl ring optionally substituted with one or moresubstituents independently selected from halogen and (1-4C)alkyl.

In one embodiment, X is CH₂, R³, R⁴ and n are as defined herein, and Yis a pyrid-2-on-3-yl ring optionally substituted with one or more groupsselected from methyl and fluoro. In one embodiment, Y is5-fluoropyridin-2(1H)-one optionally substituted with methyl. In oneembodiment, R³ is hydrogen. In another embodiment, R³ is methyl. In oneembodiment, each R⁴ is independently selected from F, Cl, Me, OH, OMe,NH₂, NHMe, CH₂OH, CHF₂ and CF₃. In one embodiment, n is 0. In oneembodiment, n is 1. In one embodiment, n is 2.

In one embodiment the ring at the 5-position of Formula I when X is CH₂include the structures:

In one embodiment, X is CH₂, such that the heterocyclic ring at the5-position of Formula I has the structure:

where R³, R⁴, Y and n are as defined herein. In one embodiment Y isphenyl optionally substituted with one or more substituentsindependently selected from halogen, -(1-4C)alkoxy, —CF₃—CHF₂, —O(1-4Calkyl)hetCyc³ or —O(1-4C alkyl)O(1-3C alkyl). In one embodiment, Y isphenyl, 3-fluorophenyl, 2,5-difluorophenyl,2-difluoromethyl-5-fluorophenyl, 2-trifluoromethyl-5-fluorophenyl,2-chloro-5-fluorophenyl, 3-chloro-5-fluorophenyl,2-methoxy-5-fluorophenyl, 3-fluoro-5-methoxyethoxyphenyl,3-fluoro-5-(2-morpholinylethoxyl)phenyl,5-fluoro-2-(2-morpholinoethoxyl)phenyl, or5-fluoro-2-methoxyethoxyphenyl. In one embodiment, Y is a 5-6 memberedheteroaryl ring having a ring heteroatom selected from N and S, whereinsaid heteroaryl ring is optionally substituted with one or moresubstituents independently selected from halogen, —O(1-4C alkyl) and(1-4C)alkyl. In one embodiment, R³ is hydrogen. In another embodiment,R³ is methyl. In one embodiment, each R⁴ is independently selected fromF, Cl, Me, OH, OMe, NH₂, NHMe, CH₂OH, CHF₂ and CF₃. In one embodiment, Yis pyrid-2-yl, 5-fluoropyrid-3-yl or 2-methoxy-5-fluoropyridy-3-yl. Inone embodiment, n is 0, 1 or 2.

Particular examples of the ring at the 5-position of Formula I when X isCH₂ include the structures:

In one embodiment, X is —CH₂CH₂—, such that the heterocyclic ring at the5-position of Formula I has the structure:

where R³, R⁴, Y and n are as defined herein. In one embodiment, Y isphenyl optionally substituted with one or more substituentsindependently selected from halogen, -(1-4C)alkoxy, —CF₃ and —CHF₂. Inone embodiment, Y is phenyl or 3-fluorophenyl. In one embodiment, Y is a5-6 membered heteroaryl ring having a ring heteroatom selected from Nand S, wherein said heteroaryl ring is optionally substituted with oneor more substituents independently selected from halogen, —O(1-4C alkyl)and (1-4C)alkyl. In one embodiment, Y is pyridyl optionally substitutedwith one or more F atoms. In one embodiment, R³ is hydrogen. In anotherembodiment, R³ is methyl. In one embodiment, n is 0, 1 or 2. In oneembodiment, n is 0. Particular examples of the ring at the 5-position ofFormula I when X is —CH₂CH₂— include the structures:

In one embodiment, X is —CH₂O—. In one embodiment, the heterocyclic ringat the 5-position of Formula I has the structure:

where R³, R⁴, Y and n are as defined herein. In one embodiment, Y isphenyl optionally substituted with one or more substituentsindependently selected from halogen, -(1-4C)alkoxy, —CF₃ and —CHF₂. Inone embodiment, Y is phenyl optionally substituted with one or moresubstituents independently selected from —F and -(1-4C)alkoxy. In oneembodiment, Y is phenyl, 3-fluorophenyl, 2,5-difluorophenyl, or2-methoxyphenyl. In one embodiment, Y is a 5-6 membered heteroaryl ringhaving a ring heteroatom selected from N and S, wherein said heteroarylring is optionally substituted with one or more substituentsindependently selected from halogen, —O(1-4C alkyl) and (1-4C)alkyl, forexample one or more halogen atoms. In one embodiment, Y is pyrid-3-yl.In one embodiment, R³ is hydrogen. In another embodiment, R³ is methyl.In one embodiment, n is 0, 1 or 2. Particular examples of the ring atthe 5-position of Formula I when X is —CH₂O— include the structures:

In one embodiment, X is —CH₂NR^(d)—. In one embodiment, the heterocyclicring at the 5-position of Formula I has the structure:

where R³, R⁴, Y, R^(d) and n are as defined herein. In one embodiment,R^(d) is H. In one embodiment, R^(d) is -(1-4C alkyl), for examplemethyl, ethyl, propyl, isopropyl, or butyl. A particular example ismethyl. In one embodiment, Y is phenyl optionally substituted with oneor more substituents independently selected from halogen, -(1-4C)alkoxy,—CF₃ and —CHF₂. In one embodiment, Y is a 5-6 membered heteroaryl ringhaving a ring heteroatom selected from N and S, wherein said heteroarylring is optionally substituted with one or more substituentsindependently selected from halogen, —O(1-4C alkyl) and (1-4C)alkyl. Inone embodiment, Y is pyridyl optionally substituted with one or more Fatoms. In one embodiment, n is 0. Particular examples of the ring at the5-position of Formula I when X is —CH₂NR^(d)— include the structures:

It will be appreciated that certain compounds according to the inventionmay contain one or more centers of asymmetry and may therefore beprepared and isolated as a mixture of isomers such as a racemic ordiastereomeric mixture, or in an enantiomerically or diastereomericallypure form.

The compounds of Formula I also include compounds of Formula Ib

and salts thereof, wherein:

R¹ is H;

R² is H, (1-6C)alkyl, (1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl or-(2-6C)dihydroxyalkyl;

Y is (i) phenyl optionally substituted with one or more substituentsindependently selected from halogen, -(1-4C)alkoxy, —CF₃—CHF₂, —O(1-4Calkyl)hetCyc³ and —O(1-4C alkyl)O(1-3C alkyl) or (ii) a 5-6 memberedheteroaryl ring having a ring heteroatom selected from N and S, whereinsaid heteroaryl ring is optionally substituted with one or moresubstituents independently selected from halogen, —O(1-4C alkyl) and(1-4C)alkyl;

hetCyc³ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O;

X is CH₂ or CH₂CH₂;

R³ is H;

each R⁴ is independently selected from halogen, -(1-4C)alkyl, —OH,-(1-4C)alkoxy, —NH₂, —NH(1-4C alkyl) and —CH₂OH; and

n is 0, 1, or 2.

In certain embodiments of Formula Ib, R² is H, (1-6C)alkyl,-(1-6C)hydroxyalkyl or -(2-6C)dihydroxyalkyl; Y is phenyl optionallysubstituted with one or more substituents independently selected from—F, —Cl, —OMe, —CF₃, —CHF₂, morpholinylethoxy and OCH₂CH₂OMe; X is CH₂and n is 0.

In certain embodiments of Formula Ib, R² is H, methyl, ethyl, isopropyl,tert-butyl, CH₂CH₂OH, or CH₂CH(OH)CH₂OH; Y is phenyl, 3-fluorophenyl,2,5-difluorophenyl, 2-chloro-5-fluorophenyl, 2-methoxyphenyl,2-methoxy-5-fluorophenyl, 2-trifluoromethyl-5-fluorophenyl,2-difluoromethyl-5-fluorophenyl, 3-chloro-5-fluorophenyl,3-fluoro-5-(2-morpholinylethoxy) phenyl,5-fluoro-2-(2-morpholinoethoxyl)phenyl, 3-fluoro-5-methoxyethoxyphenylor 5-fluoro-2-methoxyethoxyphenyl; X is CH₂; and n is 0.

In certain embodiments of Formula Ib, R² is H, (1-6C)alkyl,-(1-6C)hydroxyalkyl or -(2-6C)dihydroxyalkyl; Y is pyridyl optionallysubstituted with one or more substituents independently selected from F,OMe and Me; X is CH₂; and n is 0.

In certain embodiments of Formula Ib, R² is H, methyl, ethyl, isopropyl,tert-butyl, CH₂CH₂OH, or CH₂CH(OH)CH₂OH; Y is pyrid-2-yl, pyrid-3-yl,5-fluoropyrid-3-yl, 2-methoxy-5-fluoropyridy-3-yl or2-methyl-5-fluoropyridy-3-yl; X is CH₂; and n is 0.

Compounds of Formula I also include compounds of Formula Ic,

and salts thereof, wherein:

NR¹R² forms a 4-6 membered azacyclic ring optionally substituted withone or more substituents independently selected from (1-6C)alkyl, OH,CO₂H and (1-3C alkyl)CO₂H;

X is CH₂ or CH₂CH₂;

Y is (i) phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-4C)alkoxy, —CF₃—CHF₂, —O(1-4Calkyl)hetCyc³ and —O(1-4C alkyl)O(1-3C alkyl) or (ii) a 5-6 memberedheteroaryl ring having a ring heteroatom selected from N and S, whereinsaid heteroaryl ring is optionally substituted with one or moresubstituents independently selected from halogen, —O(1-4C alkyl) and(1-4C)alkyl;

hetCyc³ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O;

R³ is H;

each R⁴ is independently selected from halogen, -(1-4C)alkyl, —OH,-(1-4C)alkoxy, —NH₂, —NH(1-4C alkyl) and —CH₂OH; and

n is 0, 1, or 2.

In certain embodiments of Formula Ic, NR¹R² forms 4-6 membered azacyclicring optionally substituted with one or two groups independentlyselected from methyl, OH, C(═O)OH or CH₂COOH; Y is phenyl optionallysubstituted with one or more substituents independently selected from—F, —Cl, —OMe, —CF₃, —CHF₂, morpholinylethoxy and OCH₂CH₂OMe; X is CH₂;and n is 0.

In certain embodiments of Formula Ic, Y is phenyl, 3-fluorophenyl,2,5-difluorophenyl, 2-chloro-5-fluorophenyl, 2-methoxyphenyl,2-methoxy-5-fluorophenyl, 2-trifluoromethyl-5-fluorophenyl,2-difluoromethyl-5-fluorophenyl, 3-chloro-5-fluorophenyl,3-fluoro-5-(2-morpholinylethoxy) phenyl,5-fluoro-2-(2-morpholinoethoxyl)phenyl, 3-fluoro-5-methoxyethoxyphenylor 5-fluoro-2-methoxyethoxyphenyl; X is CH₂; n is 0; and NR¹R² forms 4-6membered azacyclic ring selected from one of the following structures:

In certain embodiments of Formula Ic, NR¹R² forms 4-6 membered azacyclicring optionally substituted with one or two groups independentlyselected from methyl, OH, C(═O)OH or CH₂COOH; Y is pyridyl optionallysubstituted with one or more substituents independently selected from F,OMe and Me; X is CH₂; and n is 0.

In certain embodiments of Formula Ic, Y is pyrid-2-yl, pyrid-3-yl,5-fluoropyrid-3-yl, 2-methoxy-5-fluoropyridy-3-yl or2-methyl-5-fluoropyridy-3-yl; X is CH₂; n is 0; and NR¹R² forms 4-6membered azacyclic ring selected from one of the following structures:

Compounds of Formula I also include compounds of Formula Id:

and salts thereof, wherein:

R¹ is H;

R² is Cyc¹ or a bridged 7-membered cycloalkyl ring, wherein Cyc¹ is a3-6 membered cycloalkyl ring optionally substituted with one or moresubstituents independently selected from -(1-4C alkyl), —OH, —OMe, —CO₂Hand -(1-4C alkyl)OH;

Y is (i) phenyl optionally substituted with one or more substituentsindependently selected from halogen, -(1-4C)alkoxy, —CF₃—CHF₂, —O(1-4Calkyl)hetCyc³ and —O(1-4C alkyl)O(1-3C alkyl) or (ii) a 5-6 memberedheteroaryl ring having a ring heteroatom selected from N and S, whereinsaid heteroaryl ring is optionally substituted with one or moresubstituents independently selected from halogen, —O(1-4C alkyl) and(1-4C)alkyl;

hetCyc³ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O;

X is CH₂ or CH₂CH₂;

R³ is H;

each R⁴ is independently selected from halogen, -(1-4C)alkyl, —OH,-(1-4C)alkoxy, —NH₂, —NH(1-4C alkyl) and —CH₂OH; and

n is 0, 1, or 2.

In certain embodiments of Formula Id, R² is Cyc¹ which is optionallysubstituted with one or more substituents independently selected frommethyl, —OH, —CH₂OH and —CO₂H; Y is phenyl optionally substituted withone or more substituents independently selected from —F, —Cl, —OMe,—CF₃, —CHF₂, morpholinylethoxy and OCH₂CH₂OMe; X is CH₂; and n is 0.

In certain embodiments of Formula Id, Y is phenyl, 3-fluorophenyl,2,5-difluorophenyl, 2-chloro-5-fluorophenyl, 2-methoxyphenyl,2-methoxy-5-fluorophenyl, 2-trifluoromethyl-5-fluorophenyl,2-difluoromethyl-5-fluorophenyl, 3-chloro-5-fluorophenyl,3-fluoro-5-(2-morpholinylethoxyl)phenyl,5-fluoro-2-(2-morpholinoethoxyl)phenyl, 3-fluoro-5-methoxyethoxyphenylor 5-fluoro-2-methoxyethoxyphenyl; X is CH₂, n is 0; and R² is selectedfrom the structures:

In certain embodiments of Formula Id, R² is cyclopropyl optionallysubstituted with one or two substituents independently selected frommethyl, —OH, —CH₂OH and —CO₂H; Y is phenyl optionally substituted withone or more substituents independently selected from —F, —Cl, —OMe,—CF₃, —CHF₂, morpholinylethoxy and OCH₂CH₂OMe; X is CH₂; and n is 0.

In certain embodiments of Formula Id, R² is Cyc¹ which is optionallysubstituted with one or more substituents independently selected frommethyl, —OH, —CH₂OH and —CO₂H; Y is pyridyl optionally substituted withone or more substituents independently selected from F, OMe and Me; X isCH₂; and n is 0.

In certain embodiments of Formula Id, Y is pyrid-2-yl, pyrid-3-yl,5-fluoropyrid-3-yl, 2-methoxy-5-fluoropyridy-3-yl or2-methyl-5-fluoropyridy-3-yl; X is CH₂; n is 0; and R² is selected fromthe structures:

Compounds of Formula I also include compounds of Formula Ie

and salts thereof, wherein:

R¹ is H;

R² is -(1-6C alkyl)CN, -(1-6C alkyl)SO₂NH₂, -(1-6C alkyl)NHSO₂(1-3Calkyl), -(1-6C alkyl)NH₂, -(1-6C alkyl)NH(1-4C alkyl), or -(1-6Calkyl)N(1-4C alkyl)₂;

Y is (i) phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-4C)alkoxy, —CF₃—CHF₂, —O(1-4Calkyl)hetCyc³ and —O(1-4C alkyl)O(1-3C alkyl), or (ii) a 5-6 memberedheteroaryl ring having a ring heteroatom selected from N and S, whereinsaid heteroaryl ring is optionally substituted with one or moresubstituents independently selected from halogen and —O(1-4C alkyl);

hetCyc³ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O;

X is CH₂ or CH₂CH₂;

R³ is H;

each R⁴ is independently selected from halogen, -(1-4C)alkyl, —OH,-(1-4C)alkoxy, —NH₂, —NH(1-4C alkyl) and —CH₂OH; and

n is 0, 1, or 2.

In certain embodiments of Formula Ie, Y is phenyl optionally substitutedwith one or more substituents independently selected from halogen,(1-4C)alkoxy, —CF₃—CHF₂, —O(1-4C alkyl)hetCyc³ and —O(1-4C alkyl)O(1-3Calkyl); X is CH₂; and n is 0.

In certain embodiments of Formula Ie, Y is phenyl, 3-fluorophenyl,2,5-difluorophenyl, 2-chloro-5-fluorophenyl, 2-methoxyphenyl,2-methoxy-5-fluorophenyl, 2-trifluoromethyl-5-fluorophenyl,2-difluoromethyl-5-fluorophenyl, 3-chloro-5-fluorophenyl,3-fluoro-5-(2-morpholinylethoxy)phenyl,5-fluoro-2-(2-morpholinoethoxyl)phenyl, 3-fluoro-5-methoxyethoxyphenylor 5-fluoro-2-methoxyethoxyphenyl; X is CH₂; and n is 0.

In certain embodiments of Formula Ie, Y is a 5-6 membered heteroarylring having a ring heteroatom selected from N and S, wherein saidheteroaryl ring is optionally substituted with one or more substituentsindependently selected from halogen and O(1-4C alkyl); X is CH₂; and nis 0.

In certain embodiments of Formula Ie, Y is pyrid-2-yl, pyrid-3-yl,5-fluoropyrid-3-yl, 2-methoxy-5-fluoropyridy-3-yl or2-methyl-5-fluoropyridy-3-yl; X is CH₂ and n is 0.

Compounds of Formula I also include compounds of Formula If

and salts thereof, wherein:

R¹ is H;

R² is -(1-6C alkyl)hetCyc¹, -(1-6C alkyl)hetAr¹, hetAr² or hetCyc²;

hetCyc¹ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, wherein hetCyc¹ is optionallysubstituted with oxo;

hetCyc² is a 6 membered carbon-linked heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein hetCyc² isoptionally substituted with F, SO₂NH₂, or SO₂(1-3C alkyl);

hetAr¹ is a 5-membered heteroaryl ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with(1-4C)alkyl;

hetAr² is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atomsand optionally substituted with one or more substituents independentlyselected from (1-4C)alkyl;

Y is (i) phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-4C)alkoxy, —CF₃—CHF₂, —O(1-4Calkyl)hetCyc³ and —O(1-4C alkyl)O(1-3C alkyl), or (ii) a 5-6 memberedheteroaryl ring having a ring heteroatom selected from N and S, whereinsaid heteroaryl ring is optionally substituted with one or moresubstituents independently selected from halogen and —O(1-4C alkyl);

X is CH₂ or CH₂CH₂;

R³ is H;

each R⁴ is independently selected from halogen, -(1-4C)alkyl, —OH,-(1-4C)alkoxy, —NH₂, —NH(1-4C alkyl) and —CH₂OH; and

n is 0, 1, or 2.

In certain embodiments of Formula If, R² is -(1-6C alkyl)hetAr¹ orhetAr²; Y is (i) phenyl optionally substituted with one or moresubstituents independently selected from halogen, (1-4C)alkoxy,—CF₃—CHF₂, —O(1-4C alkyl)hetCyc³ and —O(1-4C alkyl)O(1-3C alkyl); X isCH₂; and n is 0.

In certain embodiments of Formula If, R² is -(1-6C alkyl)hetAr¹ orhetAr²; hetAr¹ is a furanyl, pyrazolyl, or imidazolyl ring optionallysubstituted with -(1-4C alkyl); hetAr² is a pyridyl or pyrazolo ringoptionally substituted with one or more methyl groups; Y is phenyl,3-fluorophenyl, 2,5-difluorophenyl, 2-methoxyphenyl,2-chloro-5-fluorophenyl, 2-methoxy-5-fluorophenyl,2-trifluoromethyl-5-fluorophenyl, 2-difluoromethyl-5-fluorophenyl,3-chloro-5-fluorophenyl, 3-fluoro-5-(2-morpholinylethoxy)phenyl,5-fluoro-2-(2-morpholinoethoxyl)phenyl, 3-fluoro-5-methoxyethoxyphenylor 5-fluoro-2-methoxyethoxyphenyl; X is CH₂ and n is 0.

In certain embodiments of Formula If, R² is -(1-6C alkyl)hetAr¹ orhetAr²; Y is a 5-6 membered heteroaryl ring having a ring heteroatomselected from N and S, wherein said heteroaryl ring is optionallysubstituted with one or more substituents independently selected fromhalogen and —O(1-4C alkyl); X is CH₂; and n is 0.

In certain embodiments of Formula If, R² is -(1-6C alkyl)hetAr¹ orhetAr²; hetAr¹ is a furanyl, pyrazolyl, or imidazolyl ring optionallysubstituted with -(1-4C alkyl); hetAr² is a pyridyl or pyrazolo ringoptionally substituted with one or more methyl groups; Y is pyrid-2-yl,pyrid-3-yl, 5-fluoropyrid-3-yl, 2-methoxy-5-fluoropyridy-3-yl or2-methyl-5-fluoropyridy-3-yl; X is CH₂; and n is 0.

In certain embodiments of Formula If, R² is -(1-6C alkyl)hetCyc¹ orhetCyc²; Y is (i) phenyl optionally substituted with one or moresubstituents independently selected from halogen, (1-4C)alkoxy,—CF₃—CHF₂, —O(1-4C alkyl)hetCyc³ and —O(1-4C alkyl)O(1-3C alkyl); X isCH₂; and n is 0.

In certain embodiments of Formula If, R² is -(1-6C alkyl)hetCyc¹ orhetCyc²; hetCyc¹ is a morpholinyl or imidazolidin-2-one ring; hetCyc² isa piperidinyl or tetrahydropyranyl ring optionally substituted with F,SO₂NH₂, or SO₂(1-3C alkyl); Y is phenyl, 3-fluorophenyl,2,5-difluorophenyl, 2-chloro-5-fluorophenyl, 2-methoxyphenyl,2-methoxy-5-fluorophenyl, 2-trifluoromethyl-5-fluorophenyl,2-difluoromethyl-5-fluorophenyl, 3-chloro-5-fluorophenyl,3-fluoro-5-(2-morpholinylethoxy)phenyl,5-fluoro-2-(2-morpholinoethoxyl)phenyl, 3-fluoro-5-methoxyethoxyphenylor 5-fluoro-2-methoxyethoxyphenyl; X is CH₂; and n is 0.

In certain embodiments of Formula If, R² is hetCyc²; hetCyc² is apiperidinyl or tetrahydropyranyl ring optionally substituted with F,SO₂NH₂, or SO₂(1-3C alkyl); Y is pyrid-2-yl, pyrid-3-yl,5-fluoropyrid-3-yl, 2-methoxy-5-fluoropyridy-3-yl or2-methyl-5-fluoropyridy-3-yl; X is CH₂; and n is 0.

The compounds of Formula I also include compounds of Formula Ig

and salts thereof, wherein:

R¹ is H;

R² is —O(1-6C alkyl), —O(3-6C cycloalkyl);

Y is (i) phenyl optionally substituted with one or more substituentsindependently selected from halogen, -(1-4C)alkoxy, —CF₃—CHF₂, —O(1-4Calkyl)hetCyc³ and —O(1-4C alkyl)O(1-3C alkyl) or (ii) a 5-6 memberedheteroaryl ring having a ring heteroatom selected from N and S, whereinsaid heteroaryl ring is optionally substituted with one or moresubstituents independently selected from halogen, —O(1-4C alkyl) and(1-4C)alkyl;

hetCyc³ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O;

X is CH₂ or CH₂CH₂;

R³ is H;

each R⁴ is independently selected from halogen, -(1-4C)alkyl, —OH,-(1-4C)alkoxy, —NH₂, —NH(1-4C alkyl) and —CH₂OH; and

n is 0, 1, or 2.

In certain embodiments of Formula Ig, R² is —O(1-6C alkyl), —O(3-6Ccycloalkyl); Y is phenyl optionally substituted with one or moresubstituents independently selected from —F, —Cl, —OMe, —CF₃, —CHF₂,morpholinylethoxy and OCH₂CH₂OMe; X is CH₂ and n is 0.

In certain embodiments of Formula Ig, R² is OMe, OEt or cyclopropoxy; Yis phenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-chloro-5-fluorophenyl,2-methoxyphenyl, 2-methoxy-5-fluorophenyl,2-trifluoromethyl-5-fluorophenyl, 2-difluoromethyl-5-fluorophenyl,3-chloro-5-fluorophenyl, 3-fluoro-5-(2-morpholinylethoxy)phenyl,5-fluoro-2-(2-morpholinoethoxyl)phenyl, 3-fluoro-5-methoxyethoxyphenylor 5-fluoro-2-methoxyethoxyphenyl; X is CH₂; and n is 0.

In certain embodiments of Formula Ig, R² is —O(1-6C alkyl), —O(3-6Ccycloalkyl); Y is pyridyl optionally substituted with one or moresubstituents independently selected from F, OMe and Me; X is CH₂; and nis 0.

In certain embodiments of Formula Ig, R² is OMe, OEt or cyclopropoxy; Yis pyrid-2-yl, pyrid-3-yl, 5-fluoropyrid-3-yl,2-methoxy-5-fluoropyridy-3-yl or 2-methyl-5-fluoropyridy-3-yl; X is CH₂;and n is 0.

The compounds of Formula I also include compounds of Formula Ih

and salts thereof, wherein:

R¹ is H or -(1-6C alkyl);

R² is H, -(1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl,-(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO₂NH₂, -(1-6Calkyl)NHSO₂(1-3C alkyl), -(1-6C alkyl)NH₂, -(1-6C alkyl)NH(1-4C alkyl),-(1-6C alkyl)N(1-4C alkyl)₂, -(1-6C alkyl)hetCyc¹, -(1-6C alkyl)hetAr¹,hetAr², hetCyc², —O(1-6C alkyl), —O(3-6C cycloalkyl), or Cyc¹;

or NR¹R² forms a 4-6 membered azacyclic ring optionally substituted withone or more substituents independently selected from -(1-6C)alkyl, —OH,—CO₂H and -(1-3C alkyl)CO₂H;

Cyc¹ is a 3, 4 or 5 membered cycloalkyl ring which is optionallysubstituted with one or more substituents independently selected from-(1-4C alkyl), —OH, OMe, —CO₂H and -(1-4C alkyl)OH;

hetCyc¹ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, wherein hetCyc¹ is optionallysubstituted with oxo;

hetCyc² is a 6 membered carbon-linked heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein hetCyc² isoptionally substituted with F, SO₂NH₂, or SO₂(1-3C alkyl);

hetAr¹ is a 5-membered heteroaryl ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with(1-4C)alkyl;

hetAr² is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atomsand optionally substituted with one or more substituents independentlyselected from (1-4C)alkyl;

X is CH₂;

Y is (i) fluorophenyl optionally substituted with a substituent selectedfrom —O(1-4C alkyl)hetCyc³, -(1-4C alkyl)hetCyc³, —O(1-4C alkyl)O(1-3Calkyl) and —O(3-6C dihydroxyalkyl), (ii) pyridyl substituted with one ormore substituents independently selected from F, methyl and ethyl, or(iii) 5-fluoropyridin-2(1H)-one optionally substituted with (1-4C)alkyl;

R³ is H or -(1-4C alkyl);

each R⁴ is independently selected from halogen, -(1-4C)alkyl, —OH,-(1-4C)alkoxy, —NH₂, —NH(1-4C alkyl) and —CH₂OH; and

n is 0, 1, 2, 3, 4, 5 or 6.

In one embodiment of Formula Ih, Y is fluorophenyl optionallysubstituted with a substituent selected from —O(1-4C alkyl)hetCyc³,-(1-4C alkyl)hetCyc³, —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6Cdihydroxyalkyl).

In one embodiment of Formula Ih, Y is pyridyl substituted with one ormore substituents independently selected from F, methyl and ethyl.

In one embodiment of Formula Ih, Y is 5-fluoropyridin-2(1H)-oneoptionally substituted with (1-4C)alkyl.

In one embodiment of Formula Ih, R² is a 3, 4 or 5 membered cycloalkylring which is optionally substituted with one or more substituentsindependently selected from -(1-4C alkyl), —OH, OMe, —CO₂H and -(1-4Calkyl)OH.

In one embodiment of Formula Ih, R² is cyclopropyl optionallysubstituted with methyl, —CO₂H or —CH₂OH.

In one embodiment of Formula Ih, R⁴ is OH, F, methyl, or CH₂OH.

In one embodiment of Formula Ih, n is 0, 1 or 2.

In one embodiment of Formula Ih, R³ is hydrogen.

In one embodiment of Formula Ih, R¹ is H; R² is a 3, 4 or 5 memberedcycloalkyl ring which is optionally substituted with one or moresubstituents independently selected from -(1-4C alkyl), —OH, OMe, —CO₂Hand -(1-4C alkyl)OH; X is CH₂; Y is (i) fluorophenyl optionallysubstituted with a substituent selected from —O (1-4C alkyl)hetCyc³,O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl), (ii) pyridylsubstituted with one or more substituents independently selected from F,methyl and ethyl, or (iii) 5-fluoropyridin-2(1H)-one optionallysubstituted with (1-4C)alkyl; R³ is H, and n is 0.

It will be appreciated that certain compounds of the invention maycontain asymmetric or chiral centers, and therefore exist in differentstereoisomeric forms. It is intended that all stereoisomeric forms ofthe compounds of the invention, including but not limited to,diastereomers, enantiomers and atropisomers, as well as mixtures thereofsuch as racemic mixtures, form part of the present invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

It will also be appreciated that certain compounds of Formula I may beused as intermediates for further compounds of Formula I.

The compounds of Formula I include salts thereof. In certainembodiments, the salts are pharmaceutically acceptable salts. Inaddition, the compounds of Formula I include other salts of suchcompounds which are not necessarily pharmaceutically acceptable salts,and which may be useful as intermediates for preparing and/or purifyingcompounds of Formula I and/or for separating enantiomers of compounds ofFormula I.

It will further be appreciated that the compounds of Formula I and theirsalts may be isolated in the form of solvates, and accordingly that anysuch solvate is included within the scope of the present invention.

Compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. That is, an atom, in particular when mentioned in relation toa compound according to Formula I, comprises all isotopes and isotopicmixtures of that atom, either naturally occurring or syntheticallyproduced, either with natural abundance or in an isotopically enrichedform. For example, when hydrogen is mentioned, it is understood to referto ¹H, ²H, ³H or mixtures thereof; when carbon is mentioned, it isunderstood to refer to ¹¹C, ¹²C, ¹³C, ¹⁴C or mixtures thereof; whennitrogen is mentioned, it is understood to refer to ¹³N, ¹⁴N, ¹⁵N ormixtures thereof; when oxygen is mentioned, it is understood to refer to¹⁴O, ¹⁵O, ¹⁶O, ¹⁷O, ¹⁸O or mixtures thereof; and when fluoro ismentioned, it is understood to refer to ¹⁸F, ¹⁹F or mixtures thereof.The compounds according to the invention therefore also comprisecompounds with one or more isotopes of one or more atom, and mixturesthereof, including radioactive compounds, wherein one or morenon-radioactive atoms has been replaced by one of its radioactiveenriched isotopes. Radiolabeled compounds are useful as therapeutics,research reagents, e.g., assay reagents, and diagnostic agents, e.g., invivo imaging agents. All isotopic variations of the compounds of thepresent invention, whether radioactive or not, are intended to beencompassed within the scope of the present invention.

The term “(1-6C) alkyl” as used herein refers to saturated linear orbranched-chain monovalent hydrocarbon radicals of one to six carbonatoms, respectively. Examples include, but are not limited to, methyl,ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl,2-methyl-2-propyl, pentyl, and hexyl. The definition of “(1-6C) alkyl”likewise applies to the term “O-(1-6C alkyl)”.

The terms “(1-6C)fluoroalkyl”, “(1-6C alkyl)CN”, “(1-6C alkyl)SO₂NH₂”,“(1-6C alkyl)NHSO₂(1-3C alkyl)”, “(1-6C alkyl)NH₂”, “(1-6C alkyl)NH(1-4Calkyl)”, “(1-6C alkyl)N(1-4C alkyl)₂”, “(1-6C alkyl)hetCyc¹” and “(1-6Calkyl)hetAr¹” as used herein refer to saturated linear or branched-chainmonovalent hydrocarbon radicals of one to six carbon atoms,respectively, wherein one of the hydrogen atoms is replaced with afluoro atom, or a CN, SO₂NH₂, NHSO₂(1-3C alkyl), NH₂, NH(1-4C alkyl),N(1-4C alkyl)₂, hetCyc¹ or hetAr¹ group, respectively.

The term “(1-6C)chloroalkyl” as used herein refers to saturated linearor branched-chain monovalent hydrocarbon radicals of one to six carbonatoms, respectively, wherein one of the hydrogen atoms is replaced witha chloro atom.

The term “(1-6C)hydroxyalkyl” as used herein refers to saturated linearor branched-chain monovalent hydrocarbon radicals of one to six carbonatoms, respectively, wherein one of the hydrogen atoms are replaced witha OH group.

The term “(2-6C)dihydroxyalkyl” as used herein refers to saturatedlinear or branched-chain monovalent hydrocarbon radicals of two to sixcarbon atoms, respectively, wherein two of the hydrogen atoms arereplaced with a OH group, provided that two OH groups are not on thesame carbon.

The term “(1-6C)difluoroalkyl” as used herein refers to saturated linearor branched-chain monovalent hydrocarbon radicals of one to six carbonatoms, respectively, wherein two of the hydrogen atoms are replaced witha fluoro atom.

The term “(1-6C)trifluoroalkyl” as used herein refers to saturatedlinear or branched-chain monovalent hydrocarbon radicals of one to sixcarbon atoms, respectively, wherein three of the hydrogen atoms arereplaced with a fluoro atom.

The term “(2-6C)chlorofluoroalkyl” as used herein refers to saturatedlinear or branched-chain monovalent hydrocarbon radicals of two to sixcarbon atoms, respectively, wherein one of the hydrogen atoms isreplaced with a chloro atom and one of the hydrogen atoms is replacedwith a fluoro atom.

The term “(2-6C)difluorochloroalkyl” as used herein refers to saturatedlinear or branched-chain monovalent hydrocarbon radicals of two to sixcarbon atoms, respectively, wherein one of the hydrogen atoms isreplaced with a chloro and two of the hydrogen atoms are replaced with afluoro atom.

The term “(2-6C)chlorohydroxyalkyl” as used herein refers to a saturatedlinear or branched-chain monovalent hydrocarbon radicals of two to sixcarbon atoms, respectively, wherein one of the hydrogen atoms isreplaced with a chloro and one of the hydrogen atoms is replaced withOH.

The term “(1-6C alkyl)NHC(═O)O(1-4C alkyl)” as used herein refers tosaturated linear or branched-chain monovalent hydrocarbon radicals ofone to six carbon atoms, respectively, wherein one of the hydrogen atomsis replaced with a —NHC(═O)O(1-4C alkyl) group.

The phrase “O(1-6C alkyl) which is optionally substituted with halogen,OH or (1-4C)alkoxy” as used herein refers to a saturated linear orbranched-chain monovalent alkyl ether radical of one to six carbon atomswherein the term “alkyl” is as defined herein and the radical is on theoxygen atom, and one of the hydrogen atoms on the carbon chain isoptionally replaced with halogen, OH or (1-4C)alkoxy. Examples includemethoxy, ethoxy, propoxy, isopropoxy, and butoxy radicals optionallysubstituted with halogen, OH or (1-4C)alkoxy.

The term “O(3-6C cycloalkyl)” as used herein refers to a cycloalkylether radical wherein the term “cycloalkyl” is a 3-6 memberedcarbocyclic ring and the radical is on the oxygen atom.

The term “-(1-6C alkyl)(3-6C cycloalkyl)” as used herein refers to asaturated linear or branched-chain monovalent hydrocarbon radical of oneto six carbon atoms, respectively, wherein one of the hydrogen atoms isreplaced with a 3-6 membered carbocyclic ring.

The term “-(1-6Calkyl)(1-4C alkoxy)” as used herein refers to asaturated linear or branched-chain monovalent hydrocarbon radical of oneto six carbon atoms, respectively, wherein one of the hydrogen atoms isreplaced with an (1-4C)alkoxy group.

The term “-(1-6C hydroxyalkyl)(1-4C alkoxy)” as used herein refers to asaturated linear or branched-chain monovalent hydrocarbon radical of oneto six carbon atoms, respectively, wherein one of the hydrogen atoms isreplaced with hydroxy (OH) grou and one of the hydrogen atoms isreplaced with an (1-4C)alkoxy group.

The term “halogen” includes fluoro, chloro, bromo and iodo.

The term “pharmaceutically acceptable” indicates that the substance orcomposition is compatible chemically and/or toxicologically, with theother ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The present invention also provides a process for the preparation of acompound of Formula I or a salt thereof as defined herein, whichcomprises:

(a) reacting a corresponding compound of Formula II

or a reactive derivative thereof with an amine having the formulaHNR¹R²; or

(b) for compounds of Formula I where R¹ and R² are each hydrogen,reacting a compound of Formula III

with an inorganic acid; or

(c) for a compound of Formula I where R² is (alkyl)NHSO₂((1-3C alkyl),reacting a compound having the formula IV

with -(1-3C alkyl)SO₂Cl; or

(d) for compounds of Formula I wherein Y is 5-fluoropyridin-2(1H)-one,treating a corresponding compound having the formula VIII

with an acid at elevated temperatures; or

(e) for a compound of Formula I wherein R² is CH₂CH(OH)CH₂OH, treating acorresponding compound having the formula IX

with an acid; or

(f) for a compound of Formula I wherein Y is fluorophenyl substitutedwith —OCH₂CH(OH)CH₂OH, treating a corresponding compound having theformula X

with an acid; and

removing or adding any protecting groups if desired, and forming a saltif desired.

Referring to method (a), the coupling of the compound of formula II withan amine having the formula HNR¹R² may be performed using conventionalamide bond formation conditions, for example by reacting an amine with areactive derivative of a carboxylic acid, for example an acid halide,such as an acid chloride. When reacting the acid form of a compound ofFormula II, the reaction may be performed in the presence of a suitablecoupling agent such as 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU),O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumtetrafluoroborate (TBTU), N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarboiimide (DIEC) and any other amidecoupling reagents well known to persons skilled in the art. Suitablebases include tertiary amine bases such as diisopropylethylamine (DIEA)and triethylamine. Suitable solvents include DMF and CH₃CN.

Referring to method (b), suitable acids include strong inorganic acidssuch as sulfuric acid.

Referring to methods (d), (e) and (f), suitable acids include inorganicacids such as hydrogen halides, for example HCl.

Compounds of formula II may be prepared by coupling a correspondingcompound having formula IV

with a corresponding compound having formula V

where Z¹ is OH or a leaving group or atom and P¹ is H or a carboxylprotecting group. The leaving atom represented by Z¹ may be, forexample, a halogen atom such as a chlorine atom. In this instance, thereaction is performed in the presence of a base, such as an amine base,for example diisopropylethylamine. The reaction is convenientlyperformed at elevated temperatures, for example at 100° C. Convenientsolvents include alcohols such as butanol. When Z¹ is OH the reaction isperformed in the presence of a coupling reagent. Suitable couplingreagents when Z¹ is OH include benzotriazolyloxy tris[dimethyl-amino]phosphonium hexafluorophosphate (BOP), HATU, HBTU orTBTU. The carboxyl protecting group may be any convenient carboxylprotecting group, for example as described in Greene & Wuts, eds.,“Protecting Groups in Organic Synthesis”, John Wiley & Sons, Inc.Examples of carboxyl protecting groups include (1-6C)alkyl groups, suchas methyl, ethyl and t-butyl.

A compound of Formula V can be prepared by cyclizing a correspondingcompound of Formula VI

with (E)-ethyl 3-ethoxyacrylate to provide the compound of Formula Vwhere Z¹ is OH as shown

or when Z¹ is a leaving group or atom, converting the hydroxy group intoa leaving atom or group, for example by treating the compound of FormulaV where Z¹ is OH with POCl₃.

Compounds of Formula I where the Y group has the absolute configurationshown in Figure Ia:

are prepared by coupling a compound of Formula V with a correspondingcompound having the formula IV-A

The compound of Formula IV-A can be prepared by treating a compound ofFormula VII

where P² is an amine protecting group, with an alkyl lithium base (forexample sec-butyl lithium) in the presence of a chiral complexing agent(for example (−)-sparteine), followed by coupling with a compound havingY—Z² where Z² is a leaving group or atom, such as a halogen atom (forexample bromine) in the presence of a palladium (II) catalyst and aligand. Such enantioselective palladium-catalyzed reactions aredescribed in Campos, et al., J. Am. Chem. Soc., 2006, 128:3538-3539.Suitable catalysts include Pd(OAc)₂. Suitable ligands include phosphineligands such as t-Bu₃P—HBF₄. The amine protecting group may be anyconvenient amine protecting group, for example as described in Greene &Wuts, eds., “Protecting Groups in Organic Synthesis”, John Wiley & Sons,Inc. Examples of amine protecting groups include acyl and alkoxycarbonylgroups, such as t-butoxycarbonyl (BOC).

The compounds of the formulas II, III, and IV are also believed to benovel and are provided as further aspects of the invention.

The ability of compounds of the invention to act as TrkA inhibitors maybe demonstrated by the assays described in Examples A and B. The abilityof compounds of the invention to act as TrkB inhibitors may bedemonstrated by the assay described in Example B.

The selectivity of compounds of Formula I for TrkA versus one or moreJAK kinases was determined using the assays describes in Examples C, D,E and F.

It was unexpectedly discovered that compounds of Formula I wherein X isCH₂ are particularly selective for inhibiting TrkA activity overinhibiting the activity of one or more JAK kinases, for example JAK2, asshown in Table 1. In one embodiment, compounds of Formula I are 10-30fold more potent in inhibiting TrkA kinase activity over inhibiting Jak2kinase activity. In one embodiment, compounds of Formula I are 30-100fold more potent in inhibiting TrkA kinase activity over inhibiting Jak2kinase activity. In one embodiment, compounds of Formula I are greaterthan 100 fold more potent in inhibiting TrkA kinase activity overinhibiting Jak2 kinase activity.

Additionally, it was unexpectedly discovered that compounds of Formula Iwherein R² is a 3, 4 or 5 membered cycloalkyl ring which is optionallysubstituted with one or more substituents independently selected from-(1-4C alkyl), —OH, OMe, —CO₂H and -(1-4C alkyl)OH are particularlyselective for inhibiting TrkA activity over inhibiting the activity ofone or more JAK kinases, for example JAK2, as shown in Table 1.

Additionally, it was unexpectedly discovered that compounds of Formula Iwherein Y is (i) fluorophenyl optionally substituted with a substituentselected from —O(1-4C alkyl)hetCyc³, —O(1-4C alkyl)O(1-3C alkyl) and—O(3-6C dihydroxyalkyl), (ii) pyridyl substituted with one or moresubstituents independently selected from F, methyl and ethyl, or (iii)5-fluoropyridin-2(1H)-one optionally substituted with (1-4C)alkyl, areparticularly selective for inhibiting TrkA activity over inhibiting theactivity of one or more JAK kinases, for example JAK2, as shown in Table1.

Compounds of Formula I are useful for treating pain, including chronicand acute pain. Certain compounds which are inhibitors of TrkA and/orTrkB may be useful in the treatment of multiple types of pain includinginflammatory pain, neuropathic pain, and pain associated with cancer,surgery, and bone fracture.

In one embodiment, compounds of Formula I are useful for treating acutepain. Acute pain, as defined by the International Association for theStudy of Pain, results from disease, inflammation, or injury to tissues.This type of pain generally comes on suddenly, for example, after traumaor surgery, and may be accompanied by anxiety or stress. The cause canusually be diagnosed and treated, and the pain is confined to a givenperiod of time and severity. In some instances, it can become chronic.

In one embodiment, compounds of Formula I are useful for treatingchronic pain. Chronic pain, as defined by the International Associationfor the Study of Pain, is widely believed to represent disease itself.It can be made much worse by environmental and psychological factors.Chronic pain persists over a longer period than acute pain and isresistant to most medical treatments, generally over 3 months or more.It can and often does cause severe problems for patients.

Compounds of Formula I are also useful for treating cancer. Particularexamples include neuroblastoma, ovarian, pancreatic, colorectal andprostate cancer.

Compounds of Formula I are also useful for treating inflammation andcertain infectious diseases.

In addition, compounds of Formula I may also be used to treatinterstitial cystitis (IC), painful bladder syndrome (PBS), urinaryincontinence, asthma, anorexia, atopic dermatitis, and psoriasis.

Compounds of Formula I are also useful for treating a neurodegenerativedisease in a mammal, comprising administering to said mammal one or morecompounds of Formula I or a pharmaceutically acceptable salt thereof inan amount effective to treat or prevent said neurodegenerative disease.In one embodiment, compounds of Formula I may also be used to treatdemyelination and dysmyelination by promoting myelination, neuronalsurvival, and oligodendrocyte differentiation via blocking Sp35-TrkAinteraction. In one embodiment, the neurodegenerative disease ismultiple sclerosis. In one embodiment, the neurodegenerative disease isParkinson's disease. In one embodiment, the neurodegenerative disease isAlzheimer's disease.

As used herein, the term treatment includes prophylaxis as well astreatment of a preexisting condition. Beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, delay or slowing of disease progression, ameliorationor palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment. Those in need of treatment include those already with thecondition or disorder, as well as those prone to have the condition ordisorder or those in which the condition or disorder is to be prevented.

Accordingly, another embodiment of this invention provides a method oftreating pain in a mammal, comprising administering to said mammal oneor more compounds of Formula I or a pharmaceutically acceptable saltthereof in an amount effective to treat or prevent said pain.

Another embodiment of this invention provides a method of treatinginflammation in a mammal, comprising administering to said mammal one ormore compounds of Formula I or a pharmaceutically acceptable saltthereof in an amount effective to treat or prevent said inflammation.

Another embodiment of this invention provides a method of treating aneurodegenerative disease in a mammal, comprising administering to saidmammal one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to treat or prevent saidneurodegenerative disease.

Another embodiment of this invention provides a method of treatingTrypanosoma cruzi infection in a mammal, comprising administering tosaid mammal one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to treat or prevent saidTrypanosoma cruzi infection.

The phrase “effective amount” means an amount of compound that, whenadministered to a mammal in need of such treatment, is sufficient to (i)treat or prevent a particular disease, condition, or disorder which canbe treated with an inhibitor of TrkA and/or TrkB, (ii) attenuate,ameliorate, or eliminate one or more symptoms of the particular disease,condition, or disorder, or (iii) prevent or delay the onset of one ormore symptoms of the particular disease, condition, or disorderdescribed herein.

The amount of a compound of Formula I that will correspond to such anamount will vary depending upon factors such as the particular compound,disease condition and its severity, the identity (e.g., weight) of themammal in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art.

As used herein, the term “mammal” refers to a warm-blooded animal thathas or is at risk of developing a disease described herein and includes,but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters,and primates, including humans.

The compounds of the present invention can be used in combination withone or more additional drugs that work by the same or a differentmechanism of action. Examples include anti-inflammatory compounds,steroids (e.g., dexamethasone, cortisone and fluticasone), analgesicssuch as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen),and opioids (such as morphine), and chemotherapeutic agents.

Compounds of the invention may be administered by any convenient route,e.g. into the gastrointestinal tract (e.g. rectally or orally), thenose, lungs, musculature or vasculature, or transdermally or dermally.Compounds may be administered in any convenient administrative form,e.g. tablets, powders, capsules, solutions, dispersions, suspensions,syrups, sprays, suppositories, gels, emulsions, patches etc. Suchcompositions may contain components conventional in pharmaceuticalpreparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulkingagents, and further active agents. If parenteral administration isdesired, the compositions will be sterile and in a solution orsuspension form suitable for injection or infusion. Such compositionsform a further aspect of the invention.

According to another aspect, the present invention provides apharmaceutical composition, which comprises a compound of Formula I or apharmaceutically acceptable salt thereof, as defined hereinabove,together with a pharmaceutically acceptable diluent or carrier.

According to another embodiment, the present invention provides acompound of Formula I or a pharmaceutically acceptable salt thereof, foruse in the treatment of pain in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of inflammation in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of infectious diseases, for example Trypanosoma cruziinfection, in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of a neurodegenerative disease in a mammal.

According to a further aspect, the present invention provides the use ofa compound of Formula I or a pharmaceutically acceptable salt thereof,in the treatment of a condition selected from pain, cancer,inflammation, neurodegenerative disease or Trypanosoma cruzi infection.In one embodiment, the condition is pain. In one embodiment, thecondition is cancer. In one embodiment, the condition is inflammation.In one embodiment, the condition is a neurodegenerative disease. In oneembodiment, the condition is Trypanosoma cruzi infection.

EXAMPLES

The following examples illustrate the invention. In the examplesdescribed below, unless otherwise indicated all temperatures are setforth in degrees Celsius. Reagents were purchased from commercialsuppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge,and were used without further purification unless otherwise indicated.Tetrahydrofuran (THF), dichloromethane (DCM, methylene chloride),toluene, dimethyl formamide (DMF) and dioxane were purchased fromAldrich in Sure/Seal™ bottles and used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel or C-18 reverse phase column, or on asilica SepPak cartridge (Waters).

Biological Assays

The ability of compounds of the invention to act as TrkA inhibitors maybe demonstrated by the assays described in Examples A and B. The abilityof compounds of the invention to act as TrkB inhibitors may bedemonstrated by the assay described in Example B.

The selectivity of compounds of Formula I for inhibiting TrkA kinaseactivity over inhibiting one or more JAK kinases was determined usingthe assays describes in Examples C, D, E and F.

Example A TrkA ELISA Assay

An enzyme-linked immunosorbant assay (ELISA) was used to assess TrkAkinase activity in the presence of inhibitors Immulon 4HBX 384-wellmicrotiter plates (Thermo part #8755) were coated with a 0.025 mg/mLsolution of poly (Glu, Ala, Tyr; 6:3:1; Sigma P3899). Variousconcentrations of test compound, 2.5 nM TrkA (Invitrogen Corp.,histidine-tagged recombinant human TrkA, cytoplasmic domain), and 500 μMATP were incubated for 25 minutes at ambient temperature in the coatedplates while shaking. The assay buffer consisted of 25 mM MOPS pH 7.5,0.005% (v/v) Triton X-100 and 5 mM MgCl₂. The reaction mixture wasremoved from the plate by washing with PBS containing 0.1% (v/v) Tween20. The phosphorylated reaction product was detected using 0.2 μg/mL ofa phosphotyrosine specific monoclonal antibody (clone PY20) conjugatedto horseradish peroxidase in conjunction with the TMB PeroxidaseSubstrate System (KPL). After the addition of 1M phosphoric acid, thechromogenic substrate color intensity was quantitated via absorbance at450 nm. IC₅₀ values were calculated using either a 4 or 5-parameterlogistic curve fit and are provided in Table 1.

Example B TrkA and TrkB Omnia Assay

Trk enzymatic selectivity was assessed using Omnia™ Kinase Assayreagents from Invitrogen Corp. Enzyme (either TrkA or TrkB fromInvitrogen Corp.) and test compound (various concentrations) wereincubated for 10 minutes at ambient temperature in a 384-well whitepolypropylene plate (Nunc catalog#267462). Omnia Tyr Peptide #4 (forTrkA) or #5 (for TrkB), as well as ATP, were then added to the plate.Final concentrations were as follows: 20 nM enzyme, 500 μM of ATP forTrkA assay or 1 mM ATP for TrkB assay, 10 μM peptide substrate. Theassay buffer consisted of 25 mM MOPS pH 7.5, 0.005% (v/v) Triton X-100and 5 mM MgCl₂. The production of phosphorylated peptide was monitoredcontinuously for 70 minutes using a Molecular Devices FlexStation II³⁸⁴microplate reader (excitation=360 nm; emission=485 nm). Initial rateswere calculated from the progress curves. IC₅₀ values were calculatedfrom these rates using either a 4 or 5-parameter logistic curve fit.

In each of TrkA and TrkB Omnia assays, compounds of the invention had anaverage IC₅₀ value below 1000 nM. Certain compounds had an average IC₅₀value below 100 nM.

General JAK kinase Enzyme Inhibition Assay Method

The assays described in Examples C, D, E and F for the determination ofJAK1, JAK2, JAK3 and Tyk2 kinase activity, respectively, utilized theOmnia® Kinase fluorescence peptide substrate-based technology(Invitrogen). The specific components of the assay mixture are describedin Examples C, D and E. In each of the assays described in Examples C, Dand E, Mg²⁺ is chelated upon phosphorylation of the Omnia peptide by thekinase to form a bridge between the chelation-enhanced fluorophore Soxand the phosphate, resulting in an increase in fluorescence emission at485 nM when excited at 360 nM. The reactions were therefore read atexcitation 360 nm and emission was measured at 485 nm every 50 secondsfor 45 minutes using a PerkinElmer EnVision Multilabel Plate Reader.

The final buffer conditions for each of the JAK1, JAK2, JAK3 and Tyk2assays were as follows: 25 mM HEPES, pH 7.4, 10 mM MgCl₂, 0.01% TritonX-100 and 1 mM DTT.

IC₅₀ Determinations

Compounds were prepared at 50× the final concentration in DMSO byconducting 3-fold serial dilutions from a 500-μM or 1000-μM intermediatedilution to give a 10-point dosing curve having a high dose of 10 or 20μM. Two-μL aliquots of these were transferred to a fresh plate for aten-fold intermediate dilution with assay buffer. Five-μL aliquots ofthe diluted compounds were then transferred to 20-μL of assay mixturesdescribed in Examples C, D, E and F for a final concentration of DMSO of2%. A standard or reference compound was typically included on eachassay plate to validate that plate. For each plate, percent of control(POC) values were calculated for each well according to the followingequation:

${{POC} = {\frac{{Sample} - {\overset{\_}{X}}_{m\; i\; n}}{{{\overset{\_}{X}}_{{ma}\; x} - {\overset{\_}{X}}_{m\; i\; n}}\;} \times 100}},$

-   -   where X _(max)=Average Uninhibited Controls        -   X _(min)=Average Background            IC₅₀'s were estimated from the POC's using a standard            4-parameter logistic model:

${Y = {A + \frac{B - A}{1 + ( \frac{C}{X} )^{D}}}},$

-   -   where A=Minimum Y (Bottom Asymptote)        -   B=Maximum Y (Top Asymptote)        -   C=EC₅₀        -   D=Slope Factor        -   X=Compound Concentration (nM)        -   Y=POC

The IC₅₀ is defined as the concentration of inhibitor at which the POCequals 50 for the fitted curve.

Example C Jak1 Inhibition Assay

Compounds of Formula I were screened for their ability to inhibit Jak1using the general enzyme inhibition assay method, in which the assaymixture contained 500 μM ATP, 8 μM Omnia® Y12 peptide (Catalog # IVGNKPZ3121C; Invitrogen Corporation, Carlsbad, Calif.) and 5 nM Jak1 in atotal volume of 20 μL. GST-tagged human Jak1 kinase domain comprisingamino acids 866-1154 was purchased from Invitrogen Corporation,Carlsbad, Calif. (catalog # IVGN PV4774). Results are shown in Table 2.

Example D Jak2 Inhibition Assay

Compounds of Formula I were screened for their ability to inhibit Jak2using the general enzyme inhibition assay method, in which the assaymixture contained 500 μM ATP, 10 μM Omnia® Y7 peptide (Catalog # IVGNKNZ3071C, Invitrogen Corporation, Carlsbad, Calif.) and 4 nM Jak2 in atotal volume of 20 μL. Human Jak2 kinase domain comprising amino acids808-1132 was purchased from Invitrogen Corporation, Carlsbad, Calif.(catalog # IVGN PV4210). Results are shown in Tables 1 and 2.

Example E Jak3 Inhibition Assay

Compounds of Formula I were screened for their ability to inhibit Jak3using the general enzyme inhibition assay method, in which the assaymixture contained 500 μM ATP, 10 μM Omnia® Y7 peptide (Catalog # IVGNKNZ3071C, Invitrogen Corporation, Carlsbad, Calif.) and 1.5 nM Jak3 in atotal volume of 20 μL. GST-tagged human Jak3 kinase domain comprisingamino acids 781-1124 was purchased from Invitrogen Corporation,Carlsbad, Calif. (catalog # IVGN PV3855). Results are shown in Table 2.

Example F Tyk2 Inhibition Assay

Compounds of Formula I were screened for their ability to inhibit Tyk2using the general enzyme inhibition assay method, in which the assaymixture contained 500 μM ATP, 8 μM Omnia® Y12 peptide (Catalog # IVGNKPZ3121C; Invitrogen Corporation, Carlsbad, Calif.) and 1 nM Tyk2 in atotal volume of 20 μL. Human Tyk2 kinase domain, comprising amino acids886 to 1187 with 10 additional histidine residues (histidine tag) on thecarboxy terminus, was expressed and purified from bacculovirus in-houseat Array BioPharma Inc. (Boulder, Colo.). The histidine tag was cleavedafter purification using standard conditions. Results are shown in Table2.

Table 1 provides IC₅₀ values for compounds of the invention when testedin the assays of Examples A and D. The Jak2 enzyme IC₅₀ was designatedas >1000 nM when >50% inhibition was not observed at a 1000 nMconcentration of test compound.

TABLE 1 Jak2 Enzyme Example TrkA Enzyme IC₅₀ (nM) # IC₅₀ (nM) (%inhibition at 1000 nM) 1 0.7 >1000 (39.5) 2 0.7 >1000 (19.1) 3 2.3 >1000(10.1) 4 0.95 >1000 (18.8) 5 0.95 >1000 (14.2) 6 1.55 >1000 (12.9) 70.45 106.8 (90.0) 8 1.1 >1000 (25.7) 9 3.45 >1000 (4.6) 10 1.05 >1000(47.5) 11 777.1 >1000 (10.1) 12 238.25 >1000 (4.5) 13 0.5 >1000 (41.4)14 0.55 470 (66.7) 15 0.6 156 (83.1) 16 0.9 >1000 (31.7) 17 2.15 >1000(5.6) 18 38.3 >1000 (2.8) 19 74.25 >1000 (3.4) 20 0.6 257 (78.9) 212.95 >1000 (5.8) 22 2.1 >1000 (9.8) 23 1.1 >1000 (10.1) 24 3.6 >1000(11.5) 25 0.4 >1000 (19.4) 26 1.3 >1000 (9.9) 27 214.5 >1000 (1.3) 282.8 >1000 (5.0) 29 1.3 >1000 (13.2) 30 1.95 >1000 (25.7) 31 10.6 >1000(5.1) 32 5.3 >1000 (8.6) 33 1.5 23.4 (99.9) 34 1.1 42.3 (96.9) 35 1.2278 (77.4) 36 2.1 >1000 (22.2) 37 1.65 >1000 (25.0) 38 1.3 >1000 (18.2)39 0.7 >1000 (30.4) 40 0.8 >1000 (41.4) 41 28.9 >1000 (6.0) 4248.3 >1000 (7.7) 43 139 >1000 (4.2) 44 1.5 388 (71.5) 45 1.4 195 (84.0)46 3.3 >1000 (13.8) 47 1.5 >1000 (37.3) 48 0.6 429 (72.7) 49 4.2 >1000(17.2) 50 1.23 418 (73.7) 51 1.18 186 (82.5) 52 7.4 >1000 (9.4) 5310.4 >1000 (8.7) 54 2.25 >1000 (23.0) 55 1 >1000 (24.1) 56 2.4 >1000(28.0) 57 3.93 >1000 (9.7) 58 9.4 >1000 (4.7) 59 16.95 >1000 (14.5) 602.25 >1000 (21.1) 61 1.95 699 (54.4) 62 2.53 >1000 (35.2) 63 4.55 >1000(33.1) 64 1.6 575 (60.3) 65 0.6 >1000 (34.1) 66 0.57 >1000 (24.7) 675.1 >1000 (22.3) 68 6.6 >1000 (23.0) 69 60.3 >1000 (6.0) 70 23.95 >1000(9.0) 71 8.65 >1000 (6.2) 72 44.35 >1000 (11.7) 73 48.55 >1000 (4.9) 7412.6 >1000 (12.2) 75 6.95 >1000 (15.1) 76 90.05 >1000 (4.8) 775.37 >1000 (15.3) 78 34.85 >1000 (5.8) 79 1.3 698 (54.8) 80 1.8 869(50.7) 81 1.15 666 (54.4) 82 2.55 >1000 (10.7) 83 1.77 >1000 (26.3) 8421.05 >1000 (2.7) 85 9.38 >1000 (6.0) 86 26.7 >1000 (17.3) 87 16.1 >1000(37.2) 88 6.13 >1000 (15.1) 89 3.6 >1000 (33.1) 90 0.95 472 (67.3) 913.2 >1000 (34.9) 92 1013.3 >1000 (0.5) 93 5.1 >1000 (34.7) 94568.2 >1000 (4.4) 95 5.4 >1000 (19.2) 96 342.5 >1000 (4.8) 97 6.2 >1000(6.8) 98 9.0 >1000 (23.7) 99 7.0 >1000 (45.8) 100 4.7 >1000 (13.8) 10111.7 >1000 (26.2) 102 5.2 >1000 (17.3) 103 87.8 >1000 (4.5) 10483.1 >1000 (6.1) 105 25.4 >1000 (18.7) 106 7.7 >1000 (8) 107 16.4 >1000(7.1) 108 1191.6 >1000 (2.8) 109 36.7 >1000 (−0.3) 110 37.2 >1000 (−0.5)111 37.8 >1000 (0.1) 112 30.9 >1000 (3.2) 113 3.2 >1000 (44.6) 11429.9 >1000 (5) 115 15.3 >1000 (12.6) 116 26.2 >1000 (4.7) 117 45.0 >1000(−1.4) 118 22.5 >1000 (−4.5) 119 131.2 >1000 (1.7) 120 22.8 >1000 (2.3)121 182.5 >1000 (3.7) 122 33.2 >1000 (7.4) 123 6.4 >1000 (38.8) 124 2.9759 (53.3) 125 12.8 >1000 (6.1) 126 218.5 >1000 (−1) 127 469.8 >1000(0.2) 128 2595.0 >1000 (1.2) 129 8.0 >1000 (25.2) 130 1.7 >1000 (27.9)131 5.0 >1000 (14.6) 132 44.4 >1000 (3.7) 133 16.0 >1000 (14.4) 1347.4 >1000 (3.3) 135 142.2 >1000 (−1) 136 26.3 >1000 (4.8) 137793.7 >1000 (3.6) 138 34.8 >1000 (10) 139 32.7 >1000 (−0.4) 140 0.9 76.7(90.1) 141 9.4 >1000 (9.4) 142 12.7 >1000 (−0.9) 143 8.0 >1000 (7) 144not tested not tested 145 not tested not tested 146 not tested nottested 147 30.8 >1000 (0.9) 148 1.1 >1000 (44.3) 149 6.1 >1000 (10.2)150 5.7 >1000 (8.9) 151 1.4 >1000 (35.6) 152 18.1 >1000 (7.6) 1532.1 >1000 (33.8) 154 1.3 524 (64.4) 155 0.2 >1000 (33.3) 156 2.1 >1000(16.1) 157 2.8 >1000 (9.6) 158 9.9 >1000 (14.4) 159 4.3 >1000 (28.9) 16025.6 >1000 (8.5) 161 3.0 >1000 (27.4) 162 2.2 444 (66.2) 163 not testednot tested 164 not tested not tested 165 1.1 >1000 (26.8) 166 2.4 >1000(13.8) 167 2.2 >1000 (9.8) 168 1.2 >1000 (23.2) 169 0.9 759 (51.9) 17011.6 >1000 (0.7) 171 4.7 >1000 (7.8) 172 2.5 >1000 (11) 173 1.5 >1000(5.4) 174 16.3 >1000 (6.4) 175 12.2 >1000 (3.8) 176 27.2 >1000 (6.3) 1771.8 >1000 (26.2) 178 2.5 >1000 (16.9) 179 8.5 >1000 (−0.2) 18012.3 >1000 (−0.8) 181 17.1 >1000 (5.2) 182 11.3 >1000 (21.2) 1836.9 >1000 (−0.8) 184 7.4 >1000 (11.8) 185 8.6 >1000 (11.7) 18657.1 >1000 (10.5) 187 61.6 >1000 (9.1) 188 83.0 >1000 (9.3) 18976.4 >1000 (4.6) 190 2.4 >1000 (28.4) 191 69.5 >1000 (4.8) 192437.8 >1000 (0.3) 193 15.6 >1000 (8.4) 194 4.7 >1000 (31.2) 1957.7 >1000 (16.2) 196 6.8 >1000 (10.6) 197 4.8 >1000 (3.6) 198242.8 >1000 (1.6) 199 3.6 >1000 (38.8) 200 12.7 >1000 (12.5) 20171.8 >1000 (3.8) 202 19.3 >1000 (11.5) 203 not tested not tested 20416.6 >1000 (37) 205 14.3 >1000 (7.2) 206 3.9 >1000 (12.6) 207 33.3 >1000(0.9) 208 1.7 >1000 (21.2) 209 17.1 >1000 (5.4) 210 3.3 >1000 (32.3) 2114.2 >1000 (19.5) 212 38.0 >1000 (14.2) 213 6.8 >1000 (21.9) 2148.6 >1000 (29.7) 215 15.3 >1000 (28.3) 216 3.1 670 (54) 217 5.8 551(61.7) 218 33.9 >1000 (24.6) 219 187.7 >1000 (25.5) 220 109.9 >1000(15.2) 221 49.3 >1000 (−1.2) 222 not tested not tested 223 not testednot tested 224 not tested not tested 225 52.4 >1000 (2.7) 226 10.5 >1000(100) 227 12.3 445.8 (62.8) 228 13.0 >1000 (31.9) 229 15.9 >1000 (34.9)230 3.0 665.6 (53.3) 231 8.7 >1000 (26.6) 232 4.5 >1000 (31.9) 23375.9 >1000 (6.7) 234 10.7 >1000 (5.3) 235 2.8 311 (73.1) 236 2.2 419(69.1) 237 2.1 616 (51.9) 238 1.9 499 (58.9) 239 10.1 >1000 (15.5) 24011.3 not tested 241 21.8 not tested 242 8.9 not tested 243 9 not tested244 38.2 not tested

Representative compounds of the invention were tested in the four JakKinase enzyme assays described in Examples C, D, E and F. The IC₅₀values are shown in Table 2. These compounds were found to be even moreselective for inhibiting TrkA kinase activity over inhibiting kinaseactivity of Jak1, Jak3 and Tyk2 than over inhibiting Jak2.

TABLE 2 Jak1 Jak2 Jak3 Tyk2 TrkA IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM)IC₅₀ (% inhibition (% inhibition (% inhibition (% inhibition Ex # (nM)at 1000 nM) at 1000 nM) at 1000 nM) at 1000 nM) 301.9 >1000 >1000 >1000 >1000 (13.4) (30.4) (2.9) (11.3) 527.4 >1000 >1000 >1000 >1000 (8.6) (13.0) (0.8) (13.8) 140 0.9 54676.7 >1000 >1000 (64.2) (98.5) (20.2) (34.8) 935.1 >1000 >1000 >1000 >1000 (19.7) (42.2) (10.6) (17.2) 1067.6 >1000 >1000 >1000 >1000 (8.2) (21.0) (9.7) (14.8) 11417.1 >1000 >1000 >1000 >1000 (10.9) (15.6) (8.5) (11.4) 18129.8 >1000 >1000 >1000 >1000 (12.8) (18.1) (8.9) (10.7) 913.2 >1000 >1000 >1000 >1000 (20.3) (42.1) (8.3) (14.8) 1236.3 >1000 >1000 >1000 >1000 (22.0) (49.1) (8.9) (14.4) 124 2.9 >1000759 >1000 >1000 (36.4) (72.3) (7.2) (16.2) 1902.4 >1000 >1000 >1000 >1000 (14.3) (33.9) (7.2) (13.4) 989.0 >1000 >1000 >1000 >1000 (8.8) (27.8) (5.5) (9.2) 1944.6 >1000 >1000 >1000 >1000 (7.4) (37.6) (2.6) (8.1)

Preparation A

(R)-2-(2,5-difluorophenyl)pyrrolidine

Step A: Preparation of (R)-tert-butyl2-(2,5-difluorophenyl)pyrrolidine-1-carboxylate. A solution oftert-butyl pyrrolidine-1-carboxylate (20 g, 116.8 mmol) and(−)-sparteine (32.9, 140 mmol) in MTBE (360 mL) was cooled to −78° C.and sec-BuLi (100 mL, 140 mmol, 1.4 M in cyclohexane) was introduceddrop-wise via cannula, keeping the internal temperature under −70° C.The resulting solution was stirred for 3 hours at −78° C., followed byaddition of a solution of ZnCl₂ (93.4 mL, 93.4 mmol, 1M in Et₂O)drop-wise with rapid stirring, keeping the internal temperature below−65° C. The resulting light suspension was stirred at −78° C. for 30minutes and then warmed to ambient temperature. The resulting mixturewas sequentially charged with 2-bromo-1,4-difluorobenzene (14.5 mL, 128mmol), Pd(OAc)₂ (1.31 g, 5.8 mmol) and t-Bu₃P—HBF₄ (2.03 g, 7.0 mmol) inone portion. After stirring overnight at ambient temperature,concentrated NH₄OH (10.5 mL) was added and the reaction was stirred for1 hour. The resulting slurry was filtered through Celite and the filtercake washed with Et₂O (1 L). The filtrate was washed with a 1M aqueousHCl solution (0.5 L) and brine. The organic layer was filtered andconcentrated, and the crude product was purified by silica columnchromatography, eluting with 5-10% EtOAc/hexanes to give product(R)-tert-butyl 2-(2,5-difluorophenyl)pyrrolidine-1-carboxylate as yellowoil (23.9 g, 72% yield).

Step B: Preparation of (R)-2-(2,5-difluorophenyl)pyrrolidine. To(R)-tert-butyl 2-(2,5-difluorophenyl)pyrrolidine-1-carboxylate (23.9 g,84.4 mmol) was added 4N HCl in dioxane (56.2 mL). After stirring atambient temperature for 2 hours, ether (200 mL) was added and themixture was stirred for 10 minutes. The resulting slurry was filtered,yielding the title compound hydrochloride salt as a white solid (17.2g). To obtain the free base, the HCl salt product was dispersed in amixture of EtOAc (200 mL) and NaOH solution (100 mL, 2 N aq.) The layerswere separated and the aqueous layer was extracted with EtOAc. Thecombined organic extracts were filtered and concentrated to give thedesired product as a liquid (13.2 g, 85% yield).

The enantiomeric excess (% ee) of (R)-2-(2,5-difluorophenyl)pyrrolidinewas determined as follows: To an ethanol solution of(R)-2-(2,5-difluorophenyl)pyrrolidine was added excessN-(2,4-dinitro-5-fluorophenyl)-L-alanine amide (FDAA, Marfey's reagent).The mixture was heated to reflux for approximately two minutes. Aftercooling to ambient temperature, the reaction mixture was diluted withacetonitrile and analyzed by HPLC (YMC ODS-AQ 4.6×50 mm 3 μm 120 Åcolumn; mobile phase: 5-95% solvent B in A; solvent A: H₂O/1% iPrOH/10mM ammonium acetate, and solvent B: ACN/1% iPrOH/10 mM ammonium acetate;flow rate: 2 mL/min) The enantiomeric excess (ee %) was determined fromthe peak areas of the two diastereomeric derivatives formed. A 1:1racemic standard was prepared according the same procedure describedherein, replacing (R)-2-(2,5-difluorophenyl)pyrrolidine with(rac)-2-(2,5-difluorophenyl)pyrrolidine. The ee % of the title compoundobtained as described above was determined to be >93%.

Preparation B

Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate

Step A: Preparation of ethyl5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate. Ethyl3-amino-1H-pyrazole-4-carboxylate (25.0 g, 161 mmol) and (E)-ethyl3-ethoxyacrylate (35.8 ml, 242 mmol) were mixed in DMF (537 mL). Cesiumcarbonate (78.7 g, 242 mmol) was added and the mixture heated to 110° C.for 15 hours. The reaction mixture was cooled to ambient temperature andacidified with HOAc to pH 4. The resultant precipitate was filtered andwashed with water and EtOAc, yielding the title compound as a fluffywhite solid. Additional material was obtained by an aqueous workup. Thefiltrate was concentrated to remove the DMF, was diluted in EtOAc (500mL) and washed with H₂O. The resultant precipitate in the EtOAc layerwas filtered and washed with water and EtOAc to obtain additionalproduct. The solids were pooled and dried in vacuum to afford ethyl5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (33.3 g, 100% yield) asa fluffy white solid. MS (apci) m/z=206.2 (M−H).

Step B: Preparation of ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate. Ethyl5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (22.7 g, 110 mmol) wassuspended in phosphoryl trichloride (100 mL) and heated to reflux. Afterheating for 2 hours, the reaction mixture was cooled and concentrated toremove the excess POCl₃. The residue was diluted in DCM (100 mL) andslowly added to a flask containing ice water. The mixture was separatedand the aqueous layer extracted with DCM. The combined organics weredried with MgSO₄, filtered and concentrated to afford ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (24.2 g, 97.6% yield) asa pale yellow solid. MS (apci) m/z=225.9 (M+H).

Preparation C

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

Step A: Preparation of (R)-ethyl5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.A mixture of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate(Preparation B, 2.00 g, 8.86 mmol),(R)-2-(2,5-difluorophenyl)pyrrolidine (Preparation A, 1.62 g, 8.86mmol), diisopropylethylamine (3.09 mL, 17.7 mmol) and butan-1-ol (2.95ml, 8.86 mmol) was heated at 100° C. for 15 hours. The reaction mixturewas cooled to ambient temperature and was diluted with EtOAc (30 mL) andwater (10 mL). Undissolved solid was filtered and washed with Et₂O toafford the title compound as a light orange solid (2.13 g). The organiclayer was separated from the filtrate, washed with brine (10 mL) anddried over MgSO₄. The solution was filtered and concentrated to provideadditional solid that was purified by silica chromatography usinggradient elution with 50-100% EtOAc/hexanes. This afforded the titlecompound (0.50 g) as a light yellow solid. The combined yield was 2.63g, 79.7%. MS (apci) m/z=373.1 (M+H).

Step B: Preparation of(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. (R)-ethyl5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(2.13 g, 5.72 mmol) was suspended in EtOH (28.6 mL) and heated at 90° C.for 20 min (homogeneous). 1M aq. LiOH (11.4 mL, 11.4 mmol) was added andthe reaction mixture was heated for 15 hours at 90° C. After cooling,the reaction mixture was concentrated, diluted with water and washedwith EtOAc to remove any unreacted starting material. The aqueous layerwas then acidified to pH 1 using 2N HCl. After extracting with DCM andEtOAc, the combined organic fractions were dried with MgSO₄, filteredand concentrated to afford(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (1.82 g, 92.4%) as a light yellow solid. MS (apci) m/z=345.0 (M+H).

Preparation D

(R)-2-(3-fluorophenyl)pyrrolidine

Prepared by the method of Preparation A, substituting2-bromo-1,4-difluorobenzene with 1-bromo-3-fluorobenzene in Step A. MS(apci) m/z=166.0 (M+H). The ee % of the title compound was determined tobe 94%.

Preparation E

(R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

Step A: Preparation of (R)-ethyl5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.Prepared according to the method of Preparation C, substituting(R)-2-(2,5-difluorophenyl)pyrrolidine in Step A with(R)-2-(3-fluorophenyl)pyrrolidine. MS (apci) m/z=355.0 (M+H).

Step B: Preparation of(R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. (R)-ethyl5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(0.76 g, 2.14 mmol) was suspended in EtOH (10.7 mL) and the mixture washeated at 90° C. for 20 minutes (homogeneous). 1M aqueous LiOH (4.29 ml,4.29 mmol) was added and the reaction mixture was heated for 15 hours at90° C. After cooling, the reaction mixture was concentrated, dilutedwith water and washed with EtOAc to remove any unreacted startingmaterial. The aqueous layer was then acidified to pH 4 using 2N HCl.After extracting with DCM and EtOAc, the combined organic layers weredried with MgSO₄, filtered and concentrated to afford(R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (0.60 g, 85.7% yield) as a glassy yellow solid. MS (apci) m/z=327.0(M+H).

Preparation F

(R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine

Prepared by the method of Preparation A, substituting2-bromo-1,4-difluorobenzene with 2-bromo-4-fluoro-1-methoxybenzene inStep A. MS (apci) m/z=196.1 (M+H). The ee % of the title compound wasdetermined to be >99%.

Preparation G

(R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

In a sealed tube, ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate(Preparation B, 500 mg, 2.22 mmol),(R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine hydrochloride salt (513 mg,2.22 mmol), and diisopropylethylamine (0.774 mL, 4.43 mmol) werecombined in isopropanol (2 mL) and heated at 160° C. for 3 days. 2N NaOH(6 mL) and MeOH (5 mL) were added and the reaction mixture stirred atambient temperature for 24 hours, followed by heating to 40° C. for 3hours. The reaction was partially concentrated, treated with saturatedaqueous NH₄Cl (10 mL) and the mixture extracted with EtOAc. The combinedorganic extracts were filtered, concentrated and the residue purified byreverse phase chromatography eluting with 0-60% acetonitrile/water toyield the title compound as a pink solid (254 mg, 32.2% yield). MS(apci) m/z=357.0 (M+H).

Preparation H

(R)-3-fluoro-5-(pyrrolidin-2-yl)pyridine

Prepared by the method of Preparation A, substituting2-bromo-1,4-difluorobenzene with 3-bromo-5-fluoropyridine in Step A. MS(apci) m/z=167.1 (M+H). The ee % of the title compound was determined tobe 92%.

Preparation I

(R)-5-(2-(5-fluoropyridin-3-yl)pyrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

Step A: Preparation of ethyl5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B;0.50 g, 2.22 mmol), (R)-3-fluoro-5-(pyrrolidin-2-yl)pyridinedihydrochloride (0.53 g, 2.22 mmol) and diisopropylethylamine (1.46 mL,8.86 mmol) were combined in isopropanol (2 mL) and heated at 95° C. for70 hours. The crude product was purified by reverse phasechromatography, eluting with 0-50% acetonitrile/water to yield the titlecompound (540 mg, 68.6% yield). MS (apci) m/z=356.0 (M+H).

Step B: Preparation of5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. Ethyl5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(0.540 g, 1.52 mmol) was dissolved in MeOH (20 mL) and treated with 1NNaOH (13 mL). After stirring for 5 days, citric acid (solid) was addedto acidify the mixture to pH 4-5. Saturated aqueous NaCl (10 mL) wasadded and the reaction mixture extracted with DCM and EtOAc. Thecombined organic layers were combined to afford5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (0.49 g, 99% yield). MS (apci) m/z=328.0 (M+H).

Preparation J

(R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine

Step A: Preparation of 3-bromo-5-fluoro-2-methoxypyridine.3-Bromo-5-fluoropyridin-2(1H)-one (10.0 g, 52.1 mmol) and Ag₂CO₃ (10.0g, 36.5 mmol) were combined in toluene (100 mL) and iodomethane (3.89mL, 62.5 mmol) was added drop-wise. The reaction was stirred at ambienttemperature overnight, filtered through Celite and the solids werewashed with toluene. The filtrate was concentrated and the residue waspurified on a silica gel column (5-25% EtOAc/hexanes) to afford3-bromo-5-fluoro-2-methoxypyridine (4.70 g, 43.8%) as a clear oil.

Step B: Preparation of(R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine. Prepared by themethod of Preparation A, substituting 2-bromo-1,4-difluorobenzene with3-bromo-5-fluoro-2-methoxypyridine in Step A. MS (apci) m/z=197.1 (M+H).The ee % of the title compound was determined to be 98%.

Preparation K

(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

Step A: Preparation of (R)-ethyl5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B,0.75 g, 3.32 mmol), (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridinedihydrochloride (0.984 g, 3.66 mmol), diisopropylethylamine (2.32 mL,13.3 mmol) and n-butanol (1.11 mL) were heated at 90° C. for 48 hours.The reaction mixture was diluted with EtOAc and the mixture was washedwith water, brine and saturated NaHCO₃. The organic layer was dried withMgSO₄, filtered and concentrated afford a dark orange oil. The oil waspurified by silica chromatography, eluting with a 50-80% EtOAc/Hexanegradient, to afford (R)-ethyl5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(0.72 g, 56.2%) as a yellow foam. MS (apci) m/z=386.0 (M+H).

Step B:(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. To a suspension of (R)-ethyl5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(0.72 g, 1.868 mmol) in MeOH (9.34 mL) was added 1N LiOH (3.74 ml, 3.74mmol) and the reaction mixture heated to 70° C. for 15 hours. Aftercooling, the reaction mixture was concentrated and the resulting residuediluted in water. After acidifying with citric acid (solid), the aqueouslayer was extracted with DCM. The combined organics were dried withMgSO₄, filtered and concentrated to afforded(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (0.67 g, 100%) as a yellow solid. MS (apci) m/z=357.9 (M+H).

Preparation L

(R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidine

Prepared by the method of Preparation A, substituting2-bromo-1,4-difluorobenzene with2-bromo-4-fluoro-1-(trifluoromethyl)benzene in Step A. MS (apci)m/z=234.1 (M+H). The ee % of the title compound was determined to be90%.

Preparation M

(R)-5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

Step A: Preparation of (R)-ethyl5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate. Ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 0.51 g,2.26 mmol), (R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidinehydrochloride (0.610 g, 2.26 mmol) and diisopropylethylamine (1.12 mL,6.78 mmol) were suspended in isopropanol (2.5 mL) and heated to 120° C.for 24 hours. The reaction mixture was purified by reverse phasechromatography eluting with 0-75% acetonitrile/water to yield the titlecompound (0.92 g, 96.4% yield). MS (apci) m/z=423.0.0 (M+H).

Step B: Preparation of5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. (R)-ethyl5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(0.92 g, 2.2 mmol) was combined with 1N NaOH (25 mL) and MeOH (40 mL).The reaction mixture was stirred at ambient temperature for 20 hours,followed by heating to 40° C. until complete. Citric acid (solid) wasadded until the mixture was pH 4-5. Brine (10 mL) was added and this wasextracted with DCM and EtOAc. The combined organic layers wereconcentrated and the crude product was purified by reverse phase silicagel column chromatography eluting with 0-60% acetonitrile/water to yield5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (0.45 g, 52%). MS (apci) m/z=395.0 (M+H).

Preparation N

(R)-5-fluoro-2-methyl-3-(pyrrolidin-2-yl)pyridine

Step A: Preparation of 3-bromo-5-fluoro-2-methylpyridine:2,3-Dibromo-5-fluoropyridine (5.0 g, 19.6 mmol), Pd(PPh₃)₄ (1.13 g, 0.98mmol) and methyl boronic acid (3.52 g, 58.9 mmol) were combined indioxane (50 mL) then treated with K₂CO₃ (8.13, 58.9 mmol) and water (10mL). The mixture was purged with N₂ then heated to 110° C. in a sealedvessel for 16 hours. The cooled mixture was partitioned between water(100 mL) and EtOAc (50 mL) and the layers separated. The aqueous layerwas extracted with EtOAc (2×50 mL) and the combined organic phases werewashed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by silica gel column chromatography elutingwith 1-3% EtOAc/hexanes to afford the product as a white solid (1.20 g,32% yield). MS (apci) m/z=190.2 (M+).

Step B: Preparation of(R)-5-fluoro-2-methyl-3-(pyrrolidin-2-yl)pyridine: Prepared by themethod of Preparation A, substituting 2-bromo-1,4-difluorobenzene with3-bromo-5-fluoro-2-methylpyridine in Step A. MS (apci) m/z=181.1 (M+H).

Preparation O

(R)-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

Step A: Preparation of (R)-ethyl5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate:To a solution of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate(Preparation B, Step A, 372 mg, 1.8 mmol) in DMF (10 mL) was added(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(874 mg, 1.98 mmol). The mixture was stirred at ambient temperature for10 minutes then treated with DIEA (1.57 mL, 8.99 mmol) and(R)-5-fluoro-2-methyl-3-(pyrrolidin-2-yl)pyridine dihydrochloride (455mg, 1.80 mmol). After stirring at ambient temperature for 4 hours themixture was partitioned between 10% citric acid (50 mL) and EtOAc (50mL). The layers were separated and the aqueous layer was extracted withEtOAc (2×30 mL). The combined organic phases were washed successivelywith water (30 mL), saturated NaHCO₃ (30 mL), water (30 mL) and brine(2×30 mL), then dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silica gel column chromatography eluting with 1%MeOH/DCM to afford the product as white foam (480 mg, 72% yield). MS(apci) m/z=370.0 (M+H).

Step B: Preparation of(R)-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid: To a solution of (R)-ethyl5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(480 mg, 1.3 mmol) in a 1:1:1 mixture of THF:MeOH:water (30 mL) wasadded lithium hydroxide monohydrate (164 mg, 3.9 mmol). The mixture wasstirred at ambient temperature for 16 hours then concentrated to ⅓volume, acidified to pH 3 with 1N HCl and extracted with EtOAc (3×30mL). The combined organic phases were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated to afford the title product as awhite solid (381 mg, 86% yield). MS (apci) m/z=342.0 (M+H).

Preparation P

(R)-2-ethyl-5-fluoro-3-(pyrrolidin-2-yl)pyridine

Prepared by the method of Preparation N, substituting methyl boronicacid with ethyl boronic acid in Step A. MS (apci) m/z=195.1 (M+H).

Preparation Q

(R)-5-(2-(2-ethyl-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

Prepared by the method of Preparation O, substituting(R)-5-fluoro-2-methyl-3-(pyrrolidin-2-yl)pyridine dihydrochloride with(R)-2-ethyl-5-fluoro-3-(pyrrolidin-2-yl)pyridine dihydrochloride in StepA. MS (apci) m/z=356.0 (M+H).

Preparation R

(R)-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

Step A: Preparation of (R)-ethyl5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.To a mixture of (R)-ethyl5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(1.0 g, 2.60 mmol, Preparation K, Step A) and AcOH (7.44 mL, 130 mmol)was added HBr (4.76 mL, 33 wt % in acetic acid, 26 mmol) at ambienttemperature. The reaction mixture was heated at 90° C. for 2 hours.After cooling, the reaction mixture was diluted with EtOAc, washed withwater, saturated NaHCO3, and brine, dried with MgSO4, filtered andconcentrated. The crude material was purified by silica columnchromatography, eluting with 2-3% MeOH/DCM to yield the title product(0.73 g, 76%). MS (apci) m/z=372.0 (M+H).

Step B: Preparation of (R)-ethyl5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.To a suspension of (R)-ethyl5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(0.73 g, 1.97 mmol) in DMF (10 mL) at 0° C. was added LiH (20 mg, 2.36mmol). After stirring for 30 minutes, a solution of MeI (0.56 g, 3.93mmol) in DMF (2 mL) was added and the reaction was stirred at ambienttemperature for 17 hours. The reaction mixture was cooled to 0° C. andquenched with ice-water (30 mL). The mixture was extracted with EtOAc(3×), washed with water and brine, dried with MgSO4, filtered andconcentrated. The crude material was purified by silica columnchromatography, eluting with 2.5% MeOH/DCM to yield the title product(0.64 g, 85%). MS (apci) m/z=386.0 (M+H).

Step C: Preparation of(R)-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. Prepared by the method described in Preparation K, Step B using(R)-ethyl5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylateto yield the title compound (0.571 g, 96% yield). MS (apci) m/z=358.0(M+H).

Example 1

(R)—N-tert-butyl-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation C, 20.0 mg, 0.058 mmol) and HATU (24.3 mg, 0.064 mmol)in dry DMF (0.4 mL) was added tert-butyl amine (12.7 mg, 0.174 mmol)followed by diisopropylethylamine (22.5 mg, 0.174 mmol). The mixture wasstirred under an atmosphere of N₂ for 18 hours and was added to H₂O (3mL) and mixed. The mixture was extracted with EtOAc and combinedextracts were washed with 1M HCl, H₂O, saturated NaHCO₃ and dried overMgSO₄. The solution was eluted through a SPE SiOH column eluting firstwith 50% EtOAc-hexanes then with EtOAc. The EtOAc pool was concentratedand the residual colorless glass was treated with hexanes give a whitesuspension. The hexanes were removed, and the solid was washed withhexanes and dried in vacuum to afford the title compound as a whitesolid (20 mg, 90%). MS (apci) m/z=400.1 (M+H).

Example 2

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was prepared according to the procedure outlined forExample 1, using 2-aminopyridine (2 equivalents) heating at 90° C. for 7hours. The crude material was purified out by SiO₂ column chromatography(50% EtOAc-hexanes) to give the title compound as a white solid (45%yield). MS (apci) m/z=421.1 (M+H).

Example 3

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(3-methylpyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a suspension of(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation C, 25.0 mg, 0.072 mmol) in CCl₄ (1.0 mL) was addedthionyl chloride (0.10 mL) and the mixture heated at reflux for 4 hours.The mixture was cooled to ambient temperature and was concentrated to abrittle foam. The foam was dissolved in pyridine (2 mL),2-amino-3-methyl-pyridine (9.3 mg, 0.086 mmol) was added and the mixturewas heated at 90° C. for 20 hours. The reaction was cooled to ambienttemperature and the pyridine evaporated. The residue was partitionedinto 1M NaOH and EtOAc, mixed and the EtOAc layer removed. The aqueouslayer was extracted with EtOAc and combined EtOAc fractions were washedwith H₂O, saturated NaCl and dried over MgSO₄. The solution was filteredand concentrated, and the resulting solid was washed with dry Et₂O toafford the title compound as a white solid (7 mg, 29%). MS (apci)m/z=435.1 (M+H).

Example 4

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-morpholinoethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was prepared according to the procedure outlined forExample 1 using 2-morpholinoethanamine (1.5 equiv). The combined EtOAcextracts were washed with 1M Na₂CO₃, H₂O, saturated NaCl and dried overMgSO₄. The solution was filtered through a SPE SiOH column eluting firstwith EtOAc and then with 10% MeOH/EtOAc. The MeOH/EtOAc pool wasconcentrated and the residual colorless glass was triturated withhexanes to give fine white precipitate. The solvent was decanted and thesolid was washed with hexanes and dried in vacuum. This afforded thetitle compound as a white solid (79%). MS (apci) m/z=457.1 (M+H).

Example 5

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((5-methylfuran-2-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was prepared according to the procedure outlined forExample 1 using (5-methylfuran-2-yl)methanamine (1.5 equiv.) The driedEtOAc solution was filtered through a packed Celite plug andconcentrated. The residual colorless glass was treated with Et₂O untildissolved then diluted with hexanes to give a white suspension. Solventswere decanted, the solid washed with hexanes and dried in vacuum. Thisprovided the title compound as a white solid (43% yield). MS (apci)m/z=438.1 (M+H).

Example 6

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was prepared according to the procedure outlined forExample 3 using 1-methyl-1H-pyrazol-3-amine (1.5 equiv.) at ambienttemperature for 64 hours. The crude EtOAc solution was eluted through aSPE SiOH column (EtOAc elution) and concentrated. The residual whitesolid was washed with 10% Et₂O-hexanes and dried in vacuum to afford thetitle compound (47% yield). MS (apci) m/z=424.1 (M+H).

Example 7

5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was prepared according to the procedure outlined forExample 1 using trans-4-aminocyclohexanol (1.5 equiv). The combinedEtOAc extracts were washed with 1M Na₂CO₃, H₂O, saturated NaCl and driedover MgSO₄. The solution was filtered through a Celite plug,concentrated and the residual colorless glass was treated with hexanesto give a white suspension. The hexanes were decanted and the solidwashed with hexanes and dried in vacuum. This afforded the titlecompound as a white solid (86% yield). MS (apci) m/z=442.1 (M+H).

Example 8

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The compound was prepared according to Example 3 using2-amino-2-methylpropan-1-ol (4 equiv.). In this instance, the amine wasadded to the crude acid chloride in THF at 0° C. and the mixture wasstirred for 15 hours during which time the temperature reached ambienttemperature after 1-2 hours. The reaction mixture was partitioned intoH₂O and 50% EtOAc-hexanes. The organic layer removed and the aqueouslayer was extracted with 50% EtOAc-hexanes. The combined organicfractions were washed with 1M NaOH, H₂O and saturated NaCl. The solutionwas dried over MgSO₄ and eluted through a SPE SiOH column eluting firstwith 50% EtOAc-hexanes then with EtOAc. The EtOAc pool was concentratedand residual colorless glass was dissolved in Et₂O. Hexane was added andthe resulting white suspension was concentrated to afford the titlecompound as a white solid (57% yield). MS (apci) m/z=416.1 (M+H).

Example 9

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-methyl-1-morpholinopropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was prepared according to Example 4 using2-methyl-1-morpholinopropan-2-amine (1.5 equiv). The compound wasisolated as a white solid after SiO₂ chromatography using EtOAc forelution (83% yield). MS (apci) m/z=485.2 (M+H).

Example 10

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 1, substitutingtert-butyl amine with methyl amine, to provide the final product as awhite solid (34 mg, 83% yield). MS (apci) m/z=358.1 (M+H).

Example 11

(R)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidine-4-carboxylicacid

Step A: Preparation of (R)-ethyl1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazole[1,5-a]pyrimidine-3-carbonyl)piperidine-4-carboxylate: Preparedby the method as described in Example 1, substituting tert-butyl aminewith ethyl piperidine-4-carboxylate. The crude material was purified bypreparative TLC plate, eluting first with EtOAc and then 10% MeOH/EtOActo afford the title compound (49 mg, 88% yield). MS (apci) m/z=484.1(M+H).

Step B:(R)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidine-4-carboxylicacid: (R)-ethyl 1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidine-4-carboxylate(49 mg, 0.10 mmol) was dissolved in 1:1 THF/MeOH (1.0 mL) and 1M LiOH(0.20 mL, 0.20 mmol) was added. The mixture was stirred at ambienttemperature for 2 hours and the reaction mixture was concentrated. Theresidue was diluted in water and the mixture acidified with 2N HCl. Themixture was extracted with DCM and EtOAc. The combined organics werewashed with brine, dried with MgSO₄, filtered and concentrated. Theresidue was triturated with hexanes and the resulting white suspensionwas concentrated to afford the final product (43 mg, 92% yield) as awhite solid. MS (apci) m/z=456.1 (M+H).

Example 12

(R)-2-(1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidin-4-yl)aceticacid

Step A: Preparation of (R)-ethyl2-(1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidin-4-yl)acetate: Prepared bythe method as described in Example 11, substituting ethylpiperidine-4-carboxylate with ethyl 2-(piperidin-4-yl)acetate in step A(48 mg, 83% yield). MS (apci) m/z=498.1 (M+H).

Step B: Preparation of(R)-2-(1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidin-4-yl)aceticacid: Prepared as described in Example 11 Step B to afford the finalproduct (30 mg, 66% yield) as a white solid. MS (apci) m/z=470.1 (M+H).

Example 13

(R)—N-cyclopropyl-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 1 substituting tert-butylamine with cyclopropanamine. The crude material was purified bypreparative TLC eluting with EtOAc then 10% MeOH/EtOAc to provide thefinal product as a white solid (28 mg, 63% yield). MS (apci) m/z=384.1(M+H).

Example 14

(R)—N-cyclobutyl-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 1 substituting tert-butylamine with cyclobutanamine, to provide the final product as a whitesolid (41 mg, 88% yield). MS (apci) m/z=398.1 (M+H).

Example 15

N-((2 S)-bicyclo[2.2.1]heptan-2-yl)-5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 1, substitutingtert-butyl amine with (2R)-bicyclo[2.2.1]heptan-2-amine. The crudematerial was purified by reverse phase chromatography eluting with0-100% acetonitrile/water to yield the title compound as a white solid(47 mg, 92% yield.). MS (apci) m/z=438.2 (M+H).

Example 16

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1-(hydroxymethyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 8, using(1-aminocyclopropyl)methanol (1.5 equiv.) the procedure described forExample 8. The title compound was obtained as a white solid (35% yield).MS (apci) m/z=414.1 (M+H).

Example 17

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-hydroxy-2-methylpropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 8, using1-amino-2-methylpropan-2-ol (4.0 equiv.). The title compound wasobtained as a white solid (62% yield). MS (apci) m/z=416.1 (M+H).

Example 18

(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)((S)-3-hydroxypyrrolidin-1-yl)methanone

The title compound was prepared by the method as described in Example 1using (S)-pyrrolidin-3-ol (2.0 equiv). The EtOAc pool was concentratedand the residual colorless glass was dissolved in EtOAc. Hexanes wereadded and resulting white suspension was concentrated to give the titlecompound as a white solid (42% yield). MS (apci) m/z=414.1 (M+H).

Example 19

(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)((R)-3-hydroxypyrrolidin-1-yl)methanone

Prepared by the method as described in Example 18 using(R)-pyrrolidin-3-ol (2.0 equiv.). The title compound was obtained as awhite solid (99% yield). MS (apci) m/z=414.1 (M+H).

Example 20

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was prepared following the method of Example 1, usingtetrahydro-2H-pyran-4-amine (2.0 equiv.). The EtOAc pool wasconcentrated and the residual colorless glass was dissolved in EtOAc.Hexanes were added and resulting white suspension was concentrated togive the title compound as a white solid (68% yield). MS (apci)m/z=428.1 (M+H).

Example 21

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((1-methyl-1H-imidazol-4-yl)methyl)pyrazole[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 substituting tert-butylamine with (1-methyl-1H-imidazol-4-yl)methanamine. The crude materialwas purified by reverse phase chromatography, eluting with 0-100%acetonitrile/water to yield the title compound as a white solid (22 mg,43% yield.). MS (apci) m/z=438.1 (M+H).

Example 22

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-al-methyl-1H-pyrazol-4-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 substituting tert-butylamine with (1-methyl-1H-pyrazol-4-yl)methanamine. The crude material waspurified by reverse phase chromatography, eluting with 0-100%acetonitrile/water to yield the title compound as a white solid (34 mg,67% yield.). MS (apci) m/z=438.1 (M+H).

Example 23

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-(1-methyl-1H-imidazol-5-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 substituting tert-butylamine with 2-(1-methyl-1H-imidazol-5-yl)ethanamine. The crude materialwas purified by reverse phase chromatography, eluting with 0-100%acetonitrile/water to yield the title compound as a white solid (26 mg,49% yield.). MS (apci) m/z=452.2 (M+H).

Example 24

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-(2-oxoimidazolidin-1-yl)ethyl) pyrazole[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1, substituting tert-butylamine with 1-(2-aminoethyl)imidazolidin-2-one. The crude material waspurified by reverse phase chromatography, eluting with 0-100%acetonitrile/water to yield the title compound as a white solid (23 mg,43% yield.). MS (apci) m/z=456.1 (M+H).

Example 25

(R)—N-(2-(1H-imidazol-4-yl)ethyl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazole[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1, substituting tert-butylamine with histamine. The crude material was purified by reverse phasechromatography, eluting with 0-100% acetonitrile/water to yield thetitle compound as a white solid (17 mg, 34% yield.). MS (apci) m/z=438.2(M+H).

Example 26

5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((R)-2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1, substituting tert-butylamine with (R)-3-aminopropane-1,2-diol. The crude material was purifiedby preparative TLC using EtOAc then 10% MeOH/EtOAc for elution to affordthe title compound (19 mg, 39% yield) as a white solid. MS (apci)m/z=418.1 (M+H).

Example 27

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N,N-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 substituting tert-butylamine with dimethylamine. The crude material was purified by preparativeTLC eluting with EtOAc then 10% MeOH/EtOAc to afford the title compound(7 mg, 19% yield) as a white solid. MS (apci) m/z=372.1 (M+H).

Example 28

(R)—N-(2-(1H-imidazol-1-yl)ethyl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 substituting tert-butylamine with 2-(1H-imidazol-1-yl)ethanamine dihydrobromide. The crudematerial was purified by reverse phase chromatography eluting with0-100% acetonitrile/water to yield the title compound as a white solid(25 mg, 57% yield.). MS (apci) m/z=438.1 (M+H).

Example 29

5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((S)-2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation C, 400 mg, 1.16 mmol), HATU (486 mg, 1.28 mmol), and(S)-3-aminopropane-1,2-diol (318 mg, 3.49 mmol) in dry DMF (3.0 mL) wasstirred for 1-2 minutes at ambient temperature. Diisopropylethylamine(DIEA) (0.62 mL, 3.49 mmol) was added and the reaction was flushed withN₂, sealed and stirred at ambient temperature for 18 hours. The reactionmixture was added to H₂O (15 mL), mixed and extracted with EtOAc. Thecombined EtOAc extracts were washed with H₂O, saturated NaHCO₃ and driedover MgSO₄/activated carbon. The solution was eluted through a SiO₂column eluting first with EtOAc then 10% MeOH/EtOAc. The 10% MeOH/EtOAcpool was concentrated and the residual, colorless glass was dissolved ina minimal amount of CH₂Cl₂. Hexane was added and the resulting whitesuspension was sonicated and concentrated to give the title product as awhite solid (205 mg, 42%). MS (apci) m/z=418.1 (M+H).

Example 30

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of5-hydroxypyrazolo[1,5-a]pyrimidine-3-carbonitrile. To a mixture of5-amino-1H-pyrazole-4-carbonitrile (2.70 g, 25.0 mmol) and Cs₂CO₃ (16.3g, 50.0 mmol) in dry DMF (70 mL) was added ethyl 3-ethoxyacrylate (5.41g, 37.5 mmol) and the mixture was heated at 100° C. for 4 hours. Themixture was cooled to ambient temperature and the resultant slurry waspoured into deionized H₂O (150 mL). The resulting aqueous solution wascooled on an ice bath and concentrated HCl was added slowly with mixingto pH=3.5. The resulting precipitate was collected, washed with H₂Ofollowed by Et₂O. The solid was dried in vacuum to afford the product asa light beige powder (3.87 g, 97%). MS (apci) m/z=159.0 (M−1).

Step B: Preparation of(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile.A flask was charged with the product from Ste A (2.80 g, 17.5 mmol),benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (9.28 g, 21.0 mmol) and dry DMF (35 mL). Thesuspension was stirred at ambient temperature for 2 minutes and(R)-2-(2,5-difluorophenyl)pyrrolidine (Preparation A, 3.84 g, 21.0 mmol)and diisopropylethylamine (6.78 g, 62.5 mmol) were sequentially added(mild exotherm). The mixture was stirred at ambient temperature for 3hours and poured into H₂O (175 mL). The mixture was extracted with 50%EtOAc-hexanes and the combined organic fractions were washedsequentially with 1M HCl, H₂O, 1M Na₂CO₃ and saturated NaCl. Thesolution was dried over MgSO₄/activated carbon and filtered through ashort SiO₂ plug (350 mL course frit funnel, ¼ full of SiO₂, capped witha layer of MgSO₄) using 50% EtOAc-hexanes for elution. The solution wasconcentrated to give the title compound as a brittle white foam that wascrushed to a flowing white solid and dried in vacuum (5.50 g, 97%). MS(apci) m/z=326.2 (M+H).

Step C: Preparation of(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.The product from Step B (3.00 g, 8.85 mmol) was added in small portionsover 5 minutes to concentrated H₂SO₄ (30 mL) and the mixture was stirredat ambient temperature for 2 hours (homogeneous after 5 minutes). Thesolution was slowly added to chilled H₂O (300 mL) with stirring and themixture was extracted with EtOAc. The combined EtOAc portions werewashed with H₂O, 1M Na₂CO₃ and saturated NaCl. The EtOAc solution wasdried over MgSO₄/activated carbon, filtered through a packed Celite padand concentrated to give a white foam. The foam was dissolved in minimalCH₂Cl₂ and hexane was added to induce formation of a white precipitate.The mixture was concentrated to provide the title compound as a flowingwhite solid after drying in vacuum (2.80 g, 92%). MS (apci) m/z=344.1(M+H).

Example 31

(R)-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-hydroxyazetidin-1-yl)methanone

The title compound was prepared according to the method of Example 1,using azetidin-3-ol hydrochloride (2.0 equiv.). In this instance, thedried EtOAc solution was eluted through a SPE SiOH column eluting firstwith EtOAc then with 10% MeOH-EtOAc. The MeOH-EtOAc pool wasconcentrated to afford the title compound as a white solid (43% yield).MS (apci) m/z=400.0 (M+H).

Example 32

(R)-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone

The title compound was prepared according to the method of Example 1,using 3-methyl-azetidin-3-ol trifluoroacetate (2.0 equiv.). The driedEtOAc solution was eluted through a SPE SiOH column eluting first withEtOAc then with 10% MeOH-EtOAc. The MeOH-EtOAc pool was concentrated toafford the title compound as a white solid (71% yield). MS (apci)m/z=414.1 (M+H).

Example 33

Trans-4-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexanecarboxylicacid

Step A: Preparation of (trans)-methyl 4-aminocyclohexanecarboxylatehydrochloride. (Trans)-4-aminocyclohexanecarboxylic acid (200 mg, 1.40mmol) was suspended in MeOH (5.5 mL) and cooled to −10° C. To this wasadded SOCl₂ (204 μL, 2.79 mmol) dropwise and the mixture stirred for 15minutes. The reaction mixture was warmed to ambient temperature for 15minutes, followed by heating at reflux for 1 hour. After cooling, themixture was concentrated to afford the title compound (260 mg, 96.1%yield). MS (apci) m/z=158.0 (M+H).

Step B: Preparation of (Trans)-methyl4-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexanecarboxylate.Prepared by the method described in Example 1 substituting tert-butylamine with (trans)-methyl 4-aminocyclohexanecarboxylate hydrochloride.The crude material was purified by preparative TLC using EtOAc then 10%MeOH/EtOAc for elution to afford the title compound (38 mg, 91% yield)as a colorless oil. MS (apci) m/z=484.1 (M+H).

Step C: Preparation of(trans)-4-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexanecarboxylicacid. Prepared by the method as described in Example 11, step B toafford the title compound (29 mg, 79% yield) as a white solid. MS (apci)m/z=4701 (M+H).

Example 34

5-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 1 using(R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation G) and (trans)-4-aminocyclohexanol. The crude materialwas purified by reverse phase chromatography, eluting with 0-60%acetonitrile/water to yield the title compound as a white solid (32 mg,97% yield.). MS (apci) m/z=454.1 (M+H).

Example 35

5-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 1 using(R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation E) and (trans)-4-aminocyclohexanol to yield the titlecompound as a white solid (31 mg, 62% yield.). MS (apci) m/z=424.1(M+H).

Example 36

(R)—N-tert-butyl-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 1 using(R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation E) to yield the title compound as a white solid (33mg, 74% yield.). MS (apci) m/z=382.1 (M+H).

Example 37

(R)—N-cyclopropyl-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 1 using(R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation E) and cyclopropylamine to yield the title compound asa white solid (23 mg, 54% yield.). MS (apci) m/z=366.1 (M+H).

Example 38

(R)—N-(2-cyanopropan-2-yl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 substituting tert-butylamine with 2-amino-2-methylpropanenitrile. The crude material waspurified by preparative TLC using EtOAc then 10% MeOH/EtOAc for elutionto afford the title compound (15 mg, 41% yield) as a white solid. MS(apci) m/z=411.1 (M+H).

Example 39

(R)—N-(cyanomethyl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 substituting tert-butylamine with 2-aminoacetonitrile to provide the final product as a whitesolid (31 mg, 94% yield). MS (apci) m/z=383.0 (M+H).

Example 40

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1-fluoro-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 substituting tert-butylamine with 1-fluoro-2-methylpropan-2-amine to provide the title compoundas a white solid (31 mg, 84% yield). MS (apci) m/z=418.0 (M+H).

Example 41

N-cyclopropyl-5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of(R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanenitrile.Tert-butyldimethylsilanecarbonitrile (20.0 g, 142 mmol),(R)-2-(chloromethyl)oxirane (13.1 g, 142 mmol) and tetrabutylammoniumcyanide (0.380 g, 1.42 mmol) were mixed and heated at 100° C. for 15hours. After cooling, the crude mixture was concentrated and the residuepurified by silica chromatography eluting with 5% EtOAc/hexanes toafford (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanenitrile (17.9 g,54%) as a clear oil.

Step B: Preparation of(R)-3-(tert-butyldimethylsilyloxy)-5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole.(3-fluorophenyl)magnesium bromide (203 mL, 102 mmol, 0.5 M in ether) wasslowly added via syringe to a solution of(R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanenitrile (9.50 g, 40.6mmol) in MTBE (120 mL). The reaction was stirred for two hours and DME(35 mL) was slowly added over 15 minutes followed by EtOH (23 mL). Afterstirring overnight, brine (50 mL) and 1M NaOH (50 mL) were added and thereaction stirred for 1 hour. The reaction mixture was filtered through apad of Celite and the collected solids were washed with EtOAc. Thefiltrate was washed with 1N NaOH and brine, filtered throughphase-separator paper and concentrated to provide the title compoundthat was used directly in the next step. MS (apci) m/z=294.2 (M+H).

Step C: Preparation of(2R,4R)-4-(tert-butyldimethylsilyloxy)-2-(3-fluoro phenyl) pyrrolidine.(R)-3-(tert-butyldimethylsilyloxy)-5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole(6.21 g, 21.2 mmol) was dissolved in methanol (100 mL) and AcOH (10 mL).The reaction was cooled to −78° C. and the sodium borohydride (2.00 g,52.9 mmol) was slowly added in small portions. The reaction was allowedto warm to ambient temperature overnight. The reaction mixture wasconcentrated and the residue was diluted with EtOAc and 1N NaOH.Additional NaOH pellets were added to basify the aqueous layer. Theorganic layer was separated and the aqueous layer was extracted withEtOAc. The combined organic layers were dried with MgSO₄, filtered andconcentrated. The residual oil was purified by silica chromatographyeluting with 5% MeOH/EtOAc to afford(2R,4R)-4-(tert-butyldimethylsilyloxy)-2-(3-fluorophenyl)pyrrolidine(4.82 g, 77.1%) as a brown oil. MS (apci) m/z=296.1 (M+H).

Step D: Preparation of ethyl5-((2R,4R)-4-(tert-butyldimethylsilyloxy)-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.Prepared according to the method of Preparation C, using(2R,4R)-4-(tert-butyldimethylsilyloxy)-2-(3-fluorophenyl)pyrrolidine inStep A. MS (apci) m/z=485.1 (M+H).

Step E: Preparation of5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. Ethyl 5-((2R,4R)-4-(tert-butyldimethylsilyloxy)-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(205 mg, 0.422 mmol) was suspended in EtOH (2.0 mL) and 1M LiOH (0.845ml, 0.845 mmol) was added. The mixture was heated at reflux for 4 hoursand another portion of 1M LiOH (0.845 ml, 0.845 mmol) was added. Themixture was heated at reflux overnight, cooled to ambient temperatureand concentrated. The residue was diluted in water and the mixture wastreated with 2N HCl to achieve pH 1. The mixture was extracted with DCMand EtOAc and the combined extracts were dried with MgSO₄, filtered andconcentrated to afford5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (124 mg, 86%) as a light orange solid.

Step F: Preparation ofN-cyclopropyl-5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.Prepared by the method described in Example 1 using5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid and substituting tert-butyl amine with cyclopropylamine to providethe final product as a white solid (15 mg, 66% yield). MS (apci)m/z=382.1 (M+H).

Example 42

N-tert-butyl-5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid and tert-butyl amine to provide the final product as a white solid(24 mg, 100% yield). MS (apci) m/z=398.1 (M+H).

Example 43

5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)-N-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid and methylamine to provide the final product as a white solid (9.4mg, 45% yield). MS (apci) m/z=356.1 (M+H).

Example 44

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using1-(methylsulfonyl)piperidin-4-amine hydrochloride (1.5 equiv.). Thetitle compound was isolated as a white solid (83% yield) afterpurification by SiO₂ column (eluting with 50% EtOAc-hexanes, then EtOAc,and then 10% MeOH-EtOAc). MS (apci) m/z=505.0 (M+H).

Example 45

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1-sulfamoylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using4-aminopiperidine-1-sulfonamide (1.5 equiv.). The title compound wasisolated as a white solid (80% yield) after SiO₂ column purification(eluting with 50% EtOAc-hexanes, then EtOAc, then 10% MeOH-EtOAc). MS(apci) m/z=506.0 (M+H).

Example 46

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-(methylsulfonamido)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 usingN-(2-aminoethyl)methanesulfonamide hydrochloride (2.0 equiv.). The titlecompound was isolated as a white solid (67% yield) after SiO₂ columnpurification (eluting with 50% EtOAc-hexanes, then EtOAc, then 10%MeOH-EtOAc). MS (apci) m/z=465.0 (M+H).

Example 47

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-sulfamoylethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using2-aminoethanesulfonamide (2.0 equiv.). The title compound was isolatedas a white solid (67% yield) after SiO₂ column purification (elutingwith 50% EtOAc-hexanes, then EtOAc, then 10% MeOH-EtOAc). MS (apci)m/z=451.0 (M+H).

Example 48

(R)—N-cyclopropyl-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using(R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation G) and cyclopropylamine to yield the title compound asa white solid (19 mg, 68% yield). MS (apci) m/z=396.0 (M+H).

Example 49

(R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)-N-(2-hydroxy-2-methylpropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using(R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation G) and 1-amino-2-methylpropan-2-ol to yield the titlecompound as a white solid (17 mg, 55% yield). MS (apci) m/z=428.1 (M+H).

Example 50

5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(4-hydroxy-4-methylcyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Diastereomer 1)

Step A: Preparation of diastereomerictert-butyl-4-hydroxy-4-methylcyclohexyl carbamates. A solution oftert-butyl 4-oxocyclohexylcarbamate (1.20 g, 5.63 mmol) in dry THF (28.1mL, 5.63 mmol) was cooled to −78° C. and 3.0 M MeMgCl (5.72 mL, 17.2mmol) was added. The reaction mixture was allowed to warm to ambienttemperature and stirred for 48 hours. The reaction was quenched withsaturated NH₄Cl (10 mL) and concentrated in vacuo. The residue wasdiluted in water and DCM and solid citric acid was added until thephases separated. The organic layer was removed and washed withsaturated NaHCO₃, water and brine. The solution was dried with MgSO₄filtered and concentrated to give a mixture of diastereomeric productsas a white solid. The two diastereomers were separated using silicachromatography eluting with a gradient of 20-80% EtOAc/Hexanes: Minorisomer (45.1 mg, 7% yield), major isomer (113 mg, 18% yield). MS (apci)m/z=130.0 (M+H Boc).

Step B: Preparation of5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(4-hydroxy-4-methylcyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Diasteromer 1). The minor isomer from Step A (45.1 mg, 0.197 mmol) wasdissolved in DCM (1.0 mL) and 4N HCl in dioxane (492 μL, 1.97 mmol) wasadded. The reaction mixture was stirred at ambient temperature for 1hour and was concentrated to afford 4-amino-1-methylcyclohexanol (minorisomer). The 4-amino-1-methylcyclohexanol was reacted with(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation C) according to the procedure outlined in Example 1 toprovide the title product as a white solid (14 mg, 48% yield). MS (apci)m/z=456.1 (M+H).

Example 51

5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(4-hydroxy-4-methylcyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Diasteromer 2

The major isomer from Step A in Example 50 (45.1 mg, 0.197 mmol) wasdissolved in DCM (1.0 mL) and 4N HCl in dioxane (492 μL, 1.97 mmol) wasadded. The reaction mixture was stirred at ambient temperature for 1hour and was concentrated to afford 4-amino-1-methylcyclohexanol (majorisomer). The 4-amino-1-methylcyclohexanol was reacted with(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(Preparation C) according to the procedure outlined in Example 1 toprovide the title product as a white solid (10.7 mg, 38% yield). MS(apci) m/z=456.1 (M+H).

Example 52

(R)—N-cyclopropyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I, 30.0 mg, 0.092 mmol) and HATU (52.1 mg, 0.137 mmol)in dry DMF (0.5 mL) was added cyclopropylamine (10.5 mg, 0.183 mmol)followed by diisopropylethylamine (35.5 mg, 0.275 mmol). The mixture wasstirred under an atmosphere of N₂ for 43 hours. The crude mixture waspurified by reverse phase chromatography eluting with 0-50%acetonitrile/water to yield the title compound as a white solid (26 mg,78% yield). MS (apci) m/z=367.0 (M+H).

Example 53

(R)—N-tert-butyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 1 using(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I) and 2-methylpropan-2-amine to yield the titlecompound as a white solid (23 mg, 67% yield). MS (apci) m/z=383.1 (M+H).

Example 54

(R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)-N-(2-morpholinoethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 4, using(R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation G) and 2-morpholinoethanamine (1.5 equiv.). The titlecompound was obtained as a white solid (65% yield). MS (apci) m/z=469.1(M+H).

Example 55

N—((S)-2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method of Example 1, using(R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation G) and (S)-3-aminopropane-1,2-diol (2.0 equiv). Thecrude material was purified by SiO₂ column chromatography, eluting withEtOAc then 10% MeOH-EtOAc to afford the title compound as a white solid(53% yield). MS (apci) m/z=430.1 (M+H).

Example 56

N—((R)-2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method of Example 1, using(R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation G) and (R)-3-aminopropane-1,2-diol (2.0 equiv). Thecrude material was purified by SiO₂ column chromatography, eluting withEtOAc then 10% MeOH-EtOAc to afford the title compound as a white solid(46% yield). MS (apci) m/z=430.1 (M+H).

Example 57

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-methyl-1-(methylsulfonamido)propan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of tert-butyl 2-amino-2-methylpropylcarbamate.Tert-butyl phenyl carbonate (0.421 mL, 2.270 mmol) was added to asolution of 2-methylpropane-1,2-diamine (200 mg, 2.270 mmol) in EtOH(4.5 mL) and the reaction mixture was heated at reflux overnight. Themixture was concentrated and the residue diluted in water. The mixturewas acidified with 2N HCl to pH 4 and washed with DCM. The aqueous layerwas treated with 1M NaOH (2 mL) and extracted with DCM. The combinedorganic layers were dried with MgSO₄, filtered and concentrated toafford tert-butyl 2-amino-2-methylpropylcarbamate (158 mg, 37% yield) asa colorless oil. MS (apci) m/z=188.9 (M+H).

Step B: Preparation of (R)-tert-butyl2-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2-methylpropylcarbamate.Prepared by the method described in Example 1 using tert-butyl2-amino-2-methylpropylcarbamate to provide the title compound as acolorless oil (109 mg, 100% yield). MS (apci) m/z=515.2 (M+H).

Step C: Preparation of(R)—N-(1-amino-2-methylpropan-2-yl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamidehydrochloride. (R)-tert-butyl2-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2-methylpropylcarbamate(109 mg, 0.212 mmol) was dissolved in DCM (1.0 mL) and 4N HCl in dioxane(0.530 mL, 2.12 mmol) was added. The mixture was stirred at ambienttemperature for 4 hours and was concentrated afford the title compound(105 mg). MS (apci) m/z=415.2 (M+H).

Step D: Preparation of(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-methyl-1-(methylsulfonamido)propan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.(R)—N-(1-amino-2-methylpropan-2-yl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamidehydrochloride (24.0 mg, 0.0532 mmol) was dissolved in DCM (0.53 mL) andtriethylamine (15.2 μL, 0.109 mmol) followed by MeSO₂Cl (4.34 μL, 0.0559mmol) were added sequentially. The mixture was stirred at ambienttemperature for 2 hours and was diluted with EtOAc. The mixture waswashed with water and brine and was dried with MgSO₄. The solution wasfiltered and concentrated to afford the title compound (8.0 mg, 30%yield) as a white solid. MS (apci) m/z=493.1 (M+H).

Example 58

(R)—N-(2-amino-2-methylpropyl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1, using2-methylpropane-1,2-diamine. The crude product was purified by reversephase chromatography eluting with 0-100% acetonitrile/water to yield thetitle compound as a white solid (3.9 mg, 6.0% yield). MS (apci)m/z=415.1 (M+H).

Example 59

(R)—N-tert-butyl-5-(4,4-difluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of(R)—N-tert-butyl-5-(2-(3-fluorophenyl)-4-oxopyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide:N-tert-butyl-5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Example 42, 10 mg, 0.025 mmol) and the Dess-Martin reagent (16 mg,0.038 mmol) in DCM (2.0 mL) were stirred at ambient temperatureovernight. 1N NaOH (2.5 mL) was added and the reaction stirred for 30minutes. Brine (2.5 mL) was added and the reaction was filtered througha phase separator frit, washing with several portions of DCM. The DCMsolution was concentrated and the residue purified by reverse phasechromatography (20-70% acetonitrile/water) to provide the title compound(2.7 mg, 27% yield) as a clear oil. MS (apci) m/z=396.0 (M+H).

Step B: Preparation of(R)—N-tert-butyl-5-(4,4-difluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide:(R)—N-tert-butyl-5-(2-(3-fluorophenyl)-4-oxopyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(1.40 mg, 3.54 μmol) and bis-(2-methoxyethyl)aminosulfur trifluoride(1.57 mg, 7.08 μmol) were mixed in DCM (2.0 mL) and the reaction wasstirred at ambient temperature overnight. 1N NaOH (1.0 mL) was added andthe reaction was stirred for 30 minutes. Brine (1.0 mL) was added andthe mixture was filtered through a phase separator frit, washing withseveral portions of DCM. The DCM solution was concentrated and theresidue purified by reverse phase chromatography (0-70%acetonitrile/water) to provide the title compound (1.30 mg, 88.0% yield)as a white solid. MS (apci) m/z=418.1 (M+H).

Example 60

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1,3-dihydroxy-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared according to the method of Example 1, using2-amino-2-methylpropane-1,3-diol (2.0 equiv). The crude material waspurified by SiO₂ column chromatography, eluting with EtOAc and then 10%MeOH-EtOAc to provide the title compound as a white solid (54% yield).MS (apci) m/z=432.1 (M+H).

Example 61

5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((3S,4R)-3-fluoropiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamidehydrochloride

Step A: Preparation of (3S,4R)-tert-butyl4-(54(R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-3-fluoropiperidine-1-carboxylate.Prepared according to the method of Example 1, using (3S,4R)-tert-butyl4-amino-3-fluoropiperidine-1-carboxylate (1.5 equiv). The title compoundwas obtained as a white solid (79% yield). MS (apci) m/z=545.21 (M+H).

Step B: Preparation of 5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-f(3S,4R)-3-fluoropiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamidehydrochloride. To a solution of the title compound from Step A (50.0 mg,0.092 mmol) in EtOAc (1.5 mL) was added 4M HCl in dioxane (0.460 mL,1.85 mmol) and the mixture was stirred at ambient temperature for 6hours (white precipitate formed). The mixture was diluted with dry Et₂O(2 volumes) and sonicated to afford a fine white suspension. The solidwas collected, washed with dry Et₂O and dried under vacuum to give thetitle compound as a white solid (42 mg, 95% yield). MS (apci) m/z=445.1(M+H).

Example 62

N—((S)-2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using(R)-5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation M) and (S)-3-aminopropane-1,2-diol. The crude materialwas purified by reverse phase HPLC (0-60% acetonitrile/water) to providethe title compound (26 mg, 73% yield). MS (apci) m/z=468.1 (M+H).

Example 63

N—((R)-2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using(R)-5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation M) and (R)-3-aminopropane-1,2-diol. The crude materialwas purified by reverse phase HPLC (0-60% acetonitrile/water) to providethe title compound (34 mg, 73% yield). MS (apci) m/z=468.1 (M+H).

Example 64

(R)-5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using(R)-5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation M) and ammonium chloride. The crude material waspurified by reverse phase HPLC (0-60% acetonitrile/water) to yield thetitle compound (23 mg, 78% yield.). MS (apci) m/z=394.0 (M+H).

Example 65

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-methoxypyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 usingO-methylhydroxylamine hydrochloride (2.0 equiv). The title compound wasobtained as a white solid (53% yield). MS (apci) m/z=374.1 (M+H).

Example 66

(R)—N-(cyclopropylmethoxy)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using0-(cyclopropylmethyl)hydroxylamine (2.0 equiv). The title compound wasobtained as a white solid (31% yield). MS (apci) m/z=414.1 (M+H).

Example 67

(R)-5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of (R)-tert-butyl5-(2,5-difluorophenyl)-2,2-dimethyl pyrrolidine-1-carboxylate. Preparedby the method described in Preparation A, Step A substituting tert-butylpyrrolidine-1-carboxylate with tert-butyl2,2-dimethylpyrrolidine-1-carboxylate to provide the title compound as awhite solid (640 mg, 37% yield). MS (apci) m/z=212.1 (M+H-Boc).

Step B: Preparation of(R)-5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidine hydrochloride.Prepared by the method as described in Preparation A, Step B, using(R)-tert-butyl 5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidine-1-carboxylate to afford the title compound (420 mg, 97%yield). MS (apci) m/z=212.1 (M+H).

Step C: Preparation of (R)-ethyl5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.A sealed pressure tube was charged with (R)-5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidine HCl salt (300 mg, 1.21 mmol),diisopropylethylamine (423 μl, 2.42 mmol), ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (273 mg, 1.21 mmol) andisopropanol (2.0 mL). The tube was sealed and the mixture was heated at160° C. for 3 days. Additional ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (273 mg, 1.21 mmol) wasadded and the reaction was heated at 160° C. 2 days. The reactionmixture was concentrated and the residue purified by reverse phase HPLC(eluting with 0-60% acetonitrile/H₂O) to provide the title compound (136mg, 28%) as a beige solid. MS (apci) m/z=401.1 (M+H).

Step D: Preparation of(R)-5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. (R)-ethyl5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(136 mg, 0.340 mmol) was dissolved in MeOH (5.0 mL) and 1N NaOH (3.40mL, 3.40 mmol) was added. The reaction was stirred at ambienttemperature for 5 days and then heated at reflux for 4 hours. Thereaction mixture was cooled, poured onto a mixture of brine (10 mL) and2N HCl (5 mL) and extracted with DCM. The combined organic extracts werefiltered through PS paper and concentrated to provide the title compound(123 mg, 97% yield) as a beige solid. MS (apci) m/z=373.0 (M+H).

Step E: Preparation of(R)-5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.Prepared by the method described in Example 1 using(R)-5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid and ammonium chloride. The crude material was purified by reversephase HPLC (0-70% acetonitrile/water) to provide the title compound (8.5mg, 33% yield.). MS (apci) m/z=372.1 (M+H).

Example 68

(R)—N-cyclopropyl-5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using(R)-5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid and cyclopropylamine in Step D. The crude material was purified byreverse phase HPLC (0-75% acetonitrile/water) to provide the titlecompound (11 mg, 39% yield.). MS (apci) m/z=412.1 (M+H).

Example 69

(R)—N-(2-cyanopropan-2-yl)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I) and 2-amino-2-methylpropanenitrile to yield thetitle compound as a white solid (21 mg, 57% yield). MS (apci) m/z=394.1(M+H).

Example 70

(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 1 using(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I) and 1-(methylsulfonyl)piperidin-4-amine to yieldthe title compound as a white solid (44 mg, 100% yield). MS (apci)m/z=488.1 (M+H).

Example 71

(R)—N-(1-fluoro-2-methylpropan-2-yl)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I) and 1-fluoro-2-methylpropan-2-amine to yield thetitle compound as a white solid (37 mg, 100% yield). MS (apci) m/z=401.0(M+H).

Example 72

(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 1 using(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I) and tetrahydro-2H-pyran-4-amine to yield the titlecompound as a white solid (34 mg, 90% yield). MS (apci) m/z=411.1 (M+H).

Example 73

(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-methoxypyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method as described in Example 1 using(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I) and O-methylhydroxylamine to yield the titlecompound as a white solid (15 mg, 35% yield). MS (apci) m/z=357.0 (M+H).

Example 74

(R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a suspension of(R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation E, 50.0 mg, 0.153 mmol) in CCl₄ (1.0 mL) was addedthionyl chloride (182 mg, 1.53 mmol) and the mixture was heated atreflux for 4 hours (homogeneous after 5 minutes). The mixture was cooledto ambient temperature and was concentrated to give a brittle foam. Thefoam was dissolved in dry THF (2 mL) and dimethylaminopyridine (DMAP)(3.74 mg, 0.031 mmol) was added. Anhydrous ammonia was bubbled into themixture with stirring for 5 minutes. The reaction vessel was sealed andthe reaction was stirred at ambient temperature for 18 hours. Themixture was added to H₂O (4 mL) and extracted with EtOAc. The combinedextracts were washed with 1M Na₂CO₃, H₂O and saturated NaCl. Thesolution was dried over MgSO₄/activated carbon and filtered through aSiO₂ plug (EtOAc then 10% MeOH/EtOAc for elution). The solution wasconcentrated to give the title compound as a white solid (38 mg, 76%).MS (apci) m/z=326.0 (M+H).

Example 75

((R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)-N-methoxypyrazolo[1,5-a]pyrimidine-3-carboxamide

To a suspension of(R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation E, 50.0 mg, 0.153 mmol) in CCl₄ (1.5 mL) was addedthionyl chloride (182 mg, 1.53 mmol) and mixture heated at reflux for 4hours (homogeneous). The mixture was cooled to ambient temperature andwas concentrated to a brittle beige foam. DMAP (3.7 mg, 0.031 mmol),methylhydroxyl amine HCl (38.4 mg, 0.460 mmol) and dry THF (2 mL) wereadded and mixed. Diisopropylethylamine (79.2 mg, 0.613 mmol) was added,and the reaction flushed with N₂ and stirred at ambient temperature for18 hours. The mixture was diluted with H₂O (4 mL) and extracted withEtOAc and the combined extracts were washed with 1M Na₂CO₃, H₂O andsaturated NaCl. The solution was dried over MgSO₄/activated carbon andfiltered through a SiO₂ plug eluting with EtOAc. The mixture wasconcentrated to give a white foam that was dissolved in minimal CH₂Cl₂and treated with dry hexanes to give a fine white suspension. Themixture was concentrated to give the title compound as white solid (42mg, 77%). MS (apci) m/z=356.0 (M+H).

Example 76

(R)-5-(2-(3-fluoro-5-(2-morpholinoethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of (R)-tert-butyl2-(3-fluoro-5-hydroxyphenyl)pyrrolidine-1-carboxylate. Prepared by themethod as described in Preparation A, Step A, substituting2-bromo-1,4-difluorobenzene with 3-bromo-5-fluorophenyl acetate toafford the title compounds (10.3 g, 62% yield). MS (apci) m/z=182.1(M+H-Boc).

Step B: Preparation of (R)-3-fluoro-5-(pyrrolidin-2-yl)phenolhydrochloride. To a solution of (R)-tert-butyl2-(3-fluoro-5-hydroxyphenyl)pyrrolidine-1-carboxylate (10.3 g, 36.5mmol) in DCM (20 mL) was added 4N HCl in dioxane (36.5 mL, 146 mmol) andthe mixture was stirred at ambient temperature for 15 hours. Theresulting precipitate was filtered and washed with DCM to afford(R)-3-fluoro-5-(pyrrolidin-2-yl)phenol hydrochloride (5.81 g, 73.3%yield).

Step C: Preparation of (R)-ethyl5-(2-(3-fluoro-5-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.Prepared by the method as described in Preparation C, Step A, using(R)-2-(2,5-difluorophenyl)pyrrolidine and(R)-3-fluoro-5-(pyrrolidin-2-yl)phenol hydrochloride. The crude materialwas purified by reverse phase HPLC (0-60% acetonitrile/water) to provideyield the title compound (775 mg, 94% yield). MS (apci) m/z=370.9 (M+H).

Step D: Preparation of (R)-ethyl5-(2-(3-fluoro-5-(2-morpholinoethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.(R)-ethyl5-(2-(3-fluoro-5-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(167 mg, 0.451 mmol), 4-(2-chloroethyl)morpholine hydrochloride (168 mg,0.902 mmol), and K₂CO₃ (312 mg, 2.25 mmol) were suspended in DMF (5 mL)and stirred at ambient temperature for 15 hours. The crude reactionmixture was purified by reverse phase HPLC (0-60% acetonitrile/water) toprovide the title compound (218 mg, 100% yield). MS (apci) m/z=484.1(M+H).

Step E: Preparation of (R)-5-(2-(3-fluoro-5-(2-morpholinoethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. Preparedusing the hydrolysis conditions described in Preparation C, Step B. Thecrude material was purified by reverse phase HPLC (0-40%acetonitrile/water) to yield the title compound (208 mg, 94% yield). MS(apci) m/z=456.1 (M+H).

Step F: Preparation of (R)-5-(2-(3-fluoro-5-(2-morpholinoethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. Prepared by themethod described in Example 1 using(R)-5-(2-(3-fluoro-5-(2-morpholinoethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ammoniumchloride to yield the title compound as a white solid (19 mg, 69%yield.). MS (apci) m/z=455.1 (M+H).

Example 77

(R)—N-cyclopropyl-5-(2-(3-fluoro-5-(2-methoxyethoxyl)phenyl)pyrrolidin-1-yl)pyrazole[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of (R)-ethyl5-(2-(3-fluoro-5-(2-methoxyethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.(R)-ethyl5-(2-(3-fluoro-5-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(Example 76 Step B, 174 mg, 0.470 mmol), 1-bromo-2-methoxyethane (196mg, 1.41 mmol), and K₂CO₃ (325 mg, 2.35 mmol) were suspended in DMF (5mL) and stirred at ambient temperature for 15 hours. The crude reactionmixture was purified by reverse phase HPLC (0-60% acetonitrile/water) toprovide yield the title compound (183 mg, 91% yield). MS (apci)m/z=429.0 (M+H).

Step B: Preparation of(R)-5-(2-(3-fluoro-5-(2-methoxyethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. (R)-ethyl 5-(2-(3-fluoro-5-(2-methoxyethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(178 mg, 0.415 mmol) was suspended in a mixture of 1N NaOH (5 mL) andMeOH (5 mL). The reaction mixture was stirred at ambient temperatureuntil complete and quenched with 2N HCl (25 mL). The mixture wasextracted with ethyl acetate and the combined organic fractions wereconcentrated to give the title compound (177 mg, 100% yield). MS (apci)m/z=401.0 (M+H).

Step C: Preparation of(R)—N-cyclopropyl-5-(2-(3-fluoro-5-(2-methoxyethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.Prepared by the method described in Example 1 using(R)-5-(2-(3-fluoro-5-(2-methoxyethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid and cyclopropylamine to yield the title compound as a white solid(16 mg, 52% yield). MS (apci) m/z=440.1 (M+H).

Example 78

(R)-5-(2-(3-fluoro-5-(2-methoxyethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 77 using ammonium chloridein Step C. The crude material was purified by reverse phase HPLC (0-60%acetonitrile/water) to provide the title compound (16 mg, 53% yield.).MS (apci) m/z=400.1 (M+H).

Example 79

(R)—N-cyclopropyl-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation K) and cyclopropanamine. The combined organic extractswere concentrated and the residue was purified by reverse phase HPLC(0-70% acetonitrile/water) to provide the title compound (19 mg, 57%yield.). MS (apci) m/z=397.0 (M+H).

Example 80

(R)—N-tert-butyl-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation K). The combined organic extracts were concentratedand the residue was purified by reverse phase HPLC (0-80%acetonitrile/water) to provide the title compound (23 mg, 68% yield). MS(apci) m/z=413.0 (M+H).

Example 81

(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(1-fluoro-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation K) and 1-fluoro-2-methylpropan-2-amine. The combinedorganic extracts were concentrated and the residue was purified byreverse phase HPLC (0-90% acetonitrile/water) to provide the titlecompound (28 mg, 78% yield). MS (apci) m/z=431.0 (M+H).

Example 82

(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation K) and 7N NH₃ in MeOH. The combined organic extractswere concentrated and the residue was purified by reverse phase HPLC(0-80% acetonitrile/water) to provide the title compound (15 mg, 38%yield). MS (apci) m/z=357.0 (M+H).

Example 83

(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-methoxypyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 1 using(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation K) and O-methylhydroxylamine. The combined organicextracts were concentrated and the residue was purified by reverse phaseHPLC (0-80% acetonitrile/water) to yield the title compound (29 mg, 67%yield). MS (apci) m/z=387.0 (M+H).

Example 84

(R)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclopropanecarboxylicacid

Step A: Preparation of (R)-ethyl1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclopropanecarboxylate.Using ethyl 1-aminocyclopropanecarboxylate hydrochloride (2.0 equiv) inthe procedure described for the synthesis of Example 1, the titlecompound was obtained as a white solid (61% yield). MS (apci) m/z=456.1(M+H).

Step B: Preparation of(R)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclopropanecarboxylicacid. To a solution of the above ester (39 mg, 0.086 mmol) in 2:1THF-MeOH (1.5 mL) was added 1M aq. LiOH (0.257 mL, 257 mmol) and themixture was stirred at ambient temperature for 18 hours. The mixture wasconcentrated and the residual solid was dissolved in H₂O (3 mL). Thesolution was treated with 1M HCl to pH=3. The resulting precipitate wascollected, washed with water and dried in vacuum to yield the titlecompound as a white solid (31 mg, 83%). MS (apci) m/z=428.0 (M+H).

Example 85

(R)—N-cyclopropyl-5-(2-(3-fluoro-5-(2-morpholinoethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 76, substituting ammoniumchloride with cyclopropylamine in Step F. The crude material waspurified by reverse phase HPLC (0-60% acetonitrile/water) to provide thetitle compound (30 mg, 99% yield.). MS (apci) m/z=495.1 (M+H).

Example 86

(R)-5-(2-(5-fluoro-2-(2-morpholinoethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of (R)-tert-butyl2-(2-acetoxy-5-fluorophenyl)pyrrolidine-1-carboxylate. Prepared by themethod as described in Preparation A, Step A, substituting2-bromo-1,4-difluorobenzene with 2-bromo-4-fluorophenyl acetate toafford the title compound (5.75 g, 35% yield). MS (apci) m/z=224.1(M+H-Boc).

Step B: Preparation of (R)-4-fluoro-2-(pyrrolidin-2-yl)phenolhydrochloride. Prepared according to the procedure outlined for Example76, Step B, to afford the title compound (2.64 g, 59.3% yield). MS(apci) m/z=182.1 (M+H).

Step C: Preparation of (R)-ethyl5-(2-(3-fluoro-5-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.Prepared by the method as described in Preparation C, Step A, usingethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate and(R)-4-fluoro-2-(pyrrolidin-2-yl)phenol hydrochloride. The crude materialwas purified by reverse phase HPLC (0-65% acetonitrile/water) to providethe title compound (686 mg, 84% yield). MS (apci) m/z=371.0 (M+H).

Step D: Preparation of (R)-ethyl5-(2-(3-fluoro-5-(2-morpholinoethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.Prepared according to the procedure described in Example 76, Step D,using (R)-ethyl5-(2-(3-fluoro-5-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5pyrimidine-3-carboxylate.The crude reaction mixture was purified by reverse phase HPLC (0-60%acetonitrile/water) to provide the title compound (250 mg, 96% yield).MS (apci) m/z=484.1 (M+H).

Step E: Preparation of (R)-5-(2-(5-fluoro-2-(2-morpholinoethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acidhydrochloride. To a solution of (R)-ethyl 5-(2-(3-fluoro-5-(2-morpholinoethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(250 mg, 535 mmol) in MeOH (10 ml) was added 1N NaOH (aqueous, 6 mL).The reaction was stirred at ambient temperature for 1 week, thenconcentrated, treated with 4N HCl in dioxane (5 ml) and concentrated.The crude material was purified by reverse phase HPLC (0-50%acetonitrile/water) to yield the title compound. MS (apci) m/z=456.1(M+H).

Step F: Preparation of (R)-5-(2-(5-fluoro-2-(2-morpholinoethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. Prepared by themethod described in Example 76, Step F, using((R)-5-(2-(5-fluoro-2-(2-morpholinoethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid hydrochloride and ammonium chloride to yield the title compound asa white solid (42.2 mg, 91% yield.). MS (apci) m/z=455.1 (M+H).

Example 87

(R)—N-cyclopropyl-5-(2-(5-fluoro-2-(2-morpholinoethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 76, Step F using((R)-5-(2-(5-fluoro-2-(2-morpholinoethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid hydrochloride and cyclopropylamine to yield the title compound as awhite solid (35.4 mg, 70% yield.). MS (apci) m/z=495.1 (M+H).

Example 88

5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((S)-2,3-dihydroxypropoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide.To a suspension of(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation C, 100 mg, 0.290 mmol) in CCl₄ (1.5 mL) was addedthionyl chloride (0.10 mL, 1.37 mmol) and the mixture was heated atreflux for 2.5 hours. The mixture was cooled to ambient temperature andwas concentrated to give a residual brittle foam. The foam was dissolvedin dry THF (2.0 mL) and the solution was sequentially treated with DMAP,DIEA and (S)—O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine(85.5 mg, 0.581 mmol). The reaction was stirred at ambient temperaturefor 4.5 hours and was concentrated to approx. 0.5 mL. The mixture wasdiluted with H₂O (5 mL) and extracted with 50% EtOAc-hexanes. Thecombined extracts were washed with 1M HCl, H₂O, 1M Na₂CO₃ and saturatedNaCl. The solution was dried over MgSO₄ and activated carbon, thenfiltered through a short SiO₂ plug, eluting first with 50% EtOAc-hexanesthen 10% MeOH-EtOAc. The MeOH-EtOAc pool was concentrated to give acolorless foam. The foam was dissolved in minimal CH₂Cl₂ and treatedwith hexanes to give a white suspension. The suspension was concentratedto afford the title compound as white solid that was dried in vacuum(137 mg, 100%). MS (apci) m/z=474.1 (M+H).

Step B: Preparation of5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((S)-2,3-dihydroxypropoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide.To a solution of5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide (135 mg, 0.285 mmol) in THF (4.0mL) was added 6M HCl (1.0 mL) dropwise and the mixture was stirred atambient temperature for 1.5 hours. The reaction mixture was concentratedto approximately 1 mL and was diluted with H₂O (5 mL). The resultingmilky white mixture was extracted with EtOAc and the combined extractswere washed with 1M Na₂CO₃ and saturated NaCl. The EtOAc solution wasdried over MgSO₄ and filtered through a packed Celite pad capped with alayer of MgSO₄. The solution was concentrated to give a colorless foamthat was dissolved in minimal CH₂Cl₂ and treated with hexanes to give awhite suspension. The suspension was concentrated to give the titlecompound as a white solid that was dried in vacuum (102 mg, 82%). MS(apci) m/z=434.0 (M+H).

Example 89

(R)-5-(2-(5-fluoro-2-(2-methoxyethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of (R)-methyl5-(2-(5-fluoro-2-(2-methoxyethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate. Prepared by themethod described in Example 86, Step D, substituting4-(2-chloroethyl)morpholine hydrochloride with 1-bromo-2-methoxyethaneto afford the title compound (209 mg, 80% yield). MS (apci) m/z=415.0(M+H).

Step B: Preparation of (R)-5-(2-(5-fluoro-2-(2-methoxyethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. Preparedfrom (R)-methyl 5-(2-(5-fluoro-2-(2-methoxyethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate by the methoddescribed in Example 77, Step B to afford the title compound (163 mg,84% yield). MS (apci) m/z=401.0 (M+H).

Step C: Preparation (R)-5-(2-(5-fluoro-2-(2-methoxyethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. Prepared by themethod described in Example 76, Step F using(R)-5-(2-(5-fluoro-2-(2-methoxyethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and ammoniumchloride to yield the title compound as a white solid (32.6 mg, 55%yield.). MS (apci) m/z=400.1 (M+H).

Example 90

(R)—N-cyclopropyl-5-(2-(5-fluoro-2-(2-methoxyethoxyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 89, Step C substitutingammonium chloride with cyclopropylamine to yield the title compound as awhite solid (7.9 mg, 12% yield.). MS (apci) m/z=495.1 (M+H).

Example 91

(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of tert-butyl 1-methylcyclopropylcarbamate.Diphenylphosphoryl azide (2.63 mL, 12.2 mmol) was added to a mixture of1-methylcyclopropanecarboxylic acid (1.22 g, 12.2 mmol) and TEA (1.70mL, 12.2 mmol) in anhydrous tert-BuOH (25 mL, 12.2 mmol) under nitrogen,followed by heating first at 50° C. for 15 minutes, then at 100° C. for16 hours. After cooling to ambient temperature, the reaction wasconcentrated. The crude material was taken up in ether (50 mL), washedwith saturated NaHCO₃ and water (50 mL each), and dried (MgSO₄), givingthe crude product as white solid (0.81 g, 38% yield), which was useddirectly in the next step without further purification.

Step B: Preparation of 1-methylcyclopropanamine hydrochloride. Asolution of 1-methylcyclopropylcarbamate (250 mg, 1.46 mmol) in HCl (4Ndioxane, 3.65 mL, 14.6 mmol) was stirred at ambient temperature for 1hour. It was then concentrated, triturated with ether, and filtered,giving the product as white solid (78 mg, 50%).

Step C: Preparation of(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.To a DMF (0.6 mL) solution of(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I, 10.5 mg, 0.0321 mmol) and HATU (14.6 mg, 0.0385mmol) was added 1-methylcyclopropanamine hydrochloride (4.14 mg, 0.0385mmol) and DIEA (0.0168 mL, 0.0962 mmol). After stirring for 10 minutes,the reaction mixture was directly purified by reverse-phasechromatography (5 to 50% acetonitrile/water) to yield the final productas white solid (10 mg, 82%). LCMS (apci) m/z=381.1 (M+H).

Example 92

(R)-(5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone

Step A: Preparation of 3-methylazetidin-3-ol 2,2,2-trifluoroacetate. Toa solution of 1-benzhydryl-3-methylazetidin-3-ol (0.46 g, 1.82 mmol) inEtOH (15 mL) was added TFA (0.14 mL, 1.82 mmol) and Pd(OH)₂/C (0.127 g,0.182 mmol). The reaction was subjected to hydrogenation (50 psi) on aParr shaker at ambient temperature overnight. The reaction mixture wasfiltered, concentrated and triturated with Et₂O. The fine white solidwas filtered to yield the product as a TFA salt.

Step B: Preparation of(R)-(5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone.To a DMF (1.0 mL) solution of(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I, 85 mg, 0.26 mmol) was added HATU (118 mg, 0.31mmol) and 3-methylazetidin-3-ol 2,2,2-trifluoroacetate (63 mg, 0.31mmol) at ambient temperature, followed by addition of DIEA (0.14 mL,0.78 mmol) at 0° C. After stirring for 5 minutes at ambient temperature,the reaction was directly purified by reverse-phase chromatography (5 to45% acetonitrile/water) to yield the final product as white solid (84mg, 82%). LCMS (apci) m/z=397.1 (M+H).

Example 93

(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-isopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a DMF (1.0 mL) solution of(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I, 80 mg, 0.244 mmol) was added HATU (112 mg, 0.293mmol) and propan-2-amine (0.0250 ml, 0.293 mmol) at ambient temperature,followed by drop-wise addition of DIEA (0.128 ml, 0.733 mmol) at 0° C.After stirring for 5 minutes at ambient temperature, the reaction waspoured into 1:1 water/saturated NaHCO₃ (15 mL) and the layers wereseparated. The aqueous layer was extracted with EtOAc (3×15 mL). Thecombined organic layers were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by reverse-phase chromatography (5 to54% acetonitrile/water) to yield the final product as white solid (26mg, 29%). LCMS (apci) m/z=369.1 (M+H).

Example 94

(R)-(5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(pyrrolidin-1-yl)methanone

To a solution of(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I, 50 mg, 0.15 mmol) in anhydrous CH₂Cl₂ (2 mL) wasadded HOBt (41 mg, 0.31 mmol) followed by EDCI (88 mg, 0.46 mmol). Thesolution was stirred for 15 minutes, then treated with triethylamine (64μL, 0.46 mmol) followed by pyrrolidine (38 μL, 0.46 mmol). Afterstirring at ambient temperature overnight, the reaction mixture waspartitioned between saturated NH₄Cl (20 mL) and CH₂Cl₂ (20 mL). Theaqueous layer was extracted with CH₂Cl₂ (2×10 mL). The combined organicphases were washed with brine (10 mL), dried over Na₂SO₄ andconcentrated. The crude material was purified by silica chromatography(2 to 5% MeOH/CH₂Cl₂) to yield the final product as white solid (38 mg,65%). LCMS (apci) m/z=381.1 (M+H).

Example 95

(R)—N-(5-fluoropyridin-2-yl)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a DMF (0.25 mL) solution of(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I, 25 mg, 0.076 mmol) and HATU (35 mg, 0.092 mmol) wasadded 5-fluoropyridin-2-amine (10 mg, 0.092 mmol), followed by drop-wiseaddition of DIEA (0.040 mL, 0.23 mmol) at ambient temperature. Thereaction was heated at 70° C. overnight, cooled, and directly purifiedby reverse-phase chromatography (5 to 66% acetonitrile/water) to yieldthe final product as white solid (25 mg, 78%). LCMS (apci) m/z=422.0(M+H).

Example 96

Step A: Preparation of 3-methoxyazetidine 2,2,2-trifluoroacetate. Asolution of tert-butyl 3-methoxyazetidine-1-carboxylate (270 mg, 1.44mmol) in 1:1 TFA/DCM (1 mL) was stirred at ambient temperature for 1hour and concentrated. The crude product was directly used in the nextstep assuming quantitative yield.

Step B: Preparation of(R)-(5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-methoxyazetidin-1-yl)methanone.To a DMF (0.3 mL) solution of(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I, 30 mg, 0.092 mmol) and HATU (42 mg, 0.11 mmol) wasadded 3-methoxyazetidine 2,2,2-trifluoroacetate (22 mg, 0.11 mmol),followed by dropwise addition of DIEA (0.048 mL, 0.27 mmol). Afterstirring for 30 minutes at ambient temperature, the reaction wasdirectly purified by reverse-phase chromatography (5 to 50%acetonitrile/water) to yield the final product as white solid (25 mg,69%). LCMS (apci) m/z=397.1 (M+H).

Example 97

N-(3-chloro-2-fluoropropyl)-5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a DMF (0.3 mL) solution of(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I, 30 mg, 0.092 mmol) and HATU (42 mg, 0.11 mmol) wasadded 3-fluoroazetidine hydrochloride (12 mg, 0.11 mmol), followed byDIEA (0.048 ml, 0.27 mmol) at ambient temperature. After stirring for 2hours, the reaction was directly purified by reverse-phasechromatography (5 to 58% acetonitrile/water) to yield the product aswhite solid (8.8 mg, 23%). The isolated product was presumed to resultfrom ring-opening of the azetidine starting material. LCMS (apci)m/z=421.0 (M+H).

Example 98

(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of tert-butyl1-(trifluoromethyncyclopropylcarbamate. Diphenylphosphoryl azide (0.462mL, 2.14 mmol) was added drop-wise to a stirred mixture of1-(trifluoromethyl)cyclopropanecarboxylic acid (300 mg, 1.95 mmol), TEA(0.271 mL, 1.95 mmol) and 4 A molecular sieves in anhydrous tert-BuOH (4mL) under nitrogen at ambient temperature. The reaction was heated toreflux for 18 hours, then cooled, filtered, and concentrated, and theresidue was taken up in ether (20 mL). The organic layer was washed withsaturated NaHCO₃ and water (20 mL each), dried (Na₂SO₄), filtered andconcentrated, giving the crude product as white solid (0.32 g, 72%). Thecrude product was used directly in the next step without furtherpurification.

Step B: Preparation of 1-(trifluoromethyl)cyclopropanaminehydrochloride. A solution of tert-butyl1-(trifluoromethyl)cyclopropylcarbamate (0.3 g, 1.3 mmol) in HCl (4 Ndioxane, 6.7 mL, 27 mmol) was stirred at ambient temperature overnight.The reaction was then concentrated to yield the crude product as whitesolid, which was used directly in the next step assuming quantitativeyield.

Step C: Preparation of(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.To a DMF (0.4 mL) solution of(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I, 50 mg, 0.15 mmol) and HATU (87 mg, 0.23 mmol) wascharged 1-(trifluoromethyl)cyclopropanamine hydrochloride (37 mg, 0.23mmol), followed by drop-wise addition of DIEA (0.080 mL, 0.46 mmol).After stirring first at ambient temperature for 15 minutes and then at85° C. overnight, the reaction was cooled and directly purified byreverse-phase chromatography (5 to 60% acetonitrile/water) to yield thefinal product as off-white solid (15 mg, 23%). LCMS (apci) m/z=435.0(M+H).

The compounds listed in Table A were prepared according to the methoddescribed in Example 91, 92, 93 or 94, by reacting(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation I) with appropriate amine starting materials in thepresence of an amide coupling reagent (e.g. HATU, EDCI/HOBt) and anorganic base (e.g. DIEA, TEA) in an appropriate solvent (e.g. DMF, DCM).

TABLE A Ex. # Structure Chemical Name Data  99

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 425.1 (M + H) 100

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((cis)-4-hydroxycyclohexyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 425.1 (M + H) 101

(R)-N-cyclobutyl-5-(2-(5- fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide LCMS (apci) m/z = 381.1 (M +H) 102

(R)-5-(2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-(1-methylcyclobutyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 395.1 (M + H) 103

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((1S,2S)-2-hydroxycyclopentyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 411.1 (M + H) 104

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((1S,2R)-2-hydroxycyclopentyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 411.1 (M + H) 105

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((1S,3S)-3-hydroxycyclopentyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 411.1 (M + H) 106

(R)-N-(cyclopropylmethyl)-5-(2- (5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide LCMS (apci) m/z = 381.1 (M +H) 107

(R)-5-(2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-(1-(hydroxymethyl)cyclopropyl) pyrazolo[1,5-a]pyrimidine-3- carboxamideLCMS (apci) m/z = 397.1 (M + H) 108

(R)-(5-(2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3- hydroxyazetidin-1-yl)methanone LCMS (apci) m/z =383.1 (M + H) 109

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((S)-2-hydroxypropyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z =385.1 (M + H) 110

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((R)-2-hydroxypropyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z =385.1 (M + H) 111

(R)-5-(2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-(2-hydroxy-2-methylpropyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z= 399.1 (M + H) 112

(R)-5-(2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-(2-hydroxyethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z =371.1 (M + H) 113

N-(1-cyclopropylethyl)-5-((R)-2- (5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 395.1 (M + H) 114

(R)-5-(2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-methylpyrazolo[1,5-a]pyrimidine- 3-carboxamide LCMS (apci) m/z = 341.1(M + H) 115

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((R)-1-hydroxypropan-2-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 385.1 (M + H) 116

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((S)-1-hydroxypropan-2-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 385.1 (M + H) 117

(R)-5-(2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide LCMS (apci) m/z = 327.0 (M + H) 118

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-(1-methoxypropan-2-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 399.1 (M + H) 119

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-(2-hydroxy-3-methoxypropyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z= 415.1 (M + H) 120

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((trans)-2-hydroxycyclopentyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 411.1 (M + H) 121

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((S)-1-hydroxy-3-methylbutan-2- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamideLCMS (apci) m/z = 413.1 (M + H) 122

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((R)-1-hydroxy-3-methylbutan-2- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamideLCMS (apci) m/z = 413.1 (M + H) 123

N-((R)-1-cyclopropylethyl)-5-((R)- 2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide LCMS (apci) m/z = 395.1(M + H) 124

N-((S)-1-cyclopropylethyl)-5-((R)- 2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide LCMS (apci) m/z = 395.1(M + H) 125

(R)-5-(2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-(3-hydroxy-2,2-dimethylpropyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 413.1 (M + H) 126

(R)-azetidin-1-yl(5-(2-(5- fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3- yl)methanone LCMS (apci) m/z = 367.1 (M +H) 127

(R)-(5-(2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3- (hydroxymethyl)azetidin-1- yl)methanone LCMS (apci)m/z = 397.1 (M + H) 128

(5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)((S)-3- hydroxypyrrolidin-1-yl)methanone LCMS (apci)m/z = 397.1 (M + H) 129

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((R)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS(apci) m/z = 423.0 (M + H) 130

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((S)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS(apci) m/z = 423.0 (M + H) 131

(R)-5-(2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-(2,2,2-trifluoroethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z= 409.0 (M + H) 132

(R)-5-(2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 399.1 (M + H) 133

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((1R,2R)-2-hydroxycyclopentyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 411.1 (M + H) 134

(R)-N-(2,2-difluoroethyl)-5-(2-(5- fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide LCMS (apci) m/z = 391.0 (M +H) 135

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((1R,2S)-2-hydroxycyclopentyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 411.1 (M + H) 136

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((1R,2R)-2-hydroxycyclohexyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 425.1 (M + H) 137

(R)-(5-(2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(piperidin-1- yl)methanone LCMS (apci) m/z = 395.1 (M +H) 138

5-((R)-2-(5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((2R,3S,4S)-3-(hydroxymethyl)bicyclo[2.2.1] heptan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide LCMS (apci) m/z = 451.2 (M + H)

Example 139

(R)-(5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-hydroxyazetidin-1-yl)methanone

To a DMF (0.4 mL) solution of(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation K, 30 mg, 0.084 mmol) was added HATU (38 mg, 0.10mmol) and azetidin-3-ol hydrochloride (11 mg, 0.10 mmol) at ambienttemperature, followed by dropwise addition of DIEA (0.044 ml, 0.25 mmol)at 0° C. After stirring for 20 minutes at ambient temperature, thereaction was directly purified by reverse-phase chromatography (5 to 50%acetonitrile/water) to yield the final product as white solid (26 mg,75%). LCMS (apci) m/z=413.1 (M+H).

Example 140

5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation K, 30 mg, 0.084 mmol) in anhydrous CH₂Cl₂ (2 mL) wasadded HOBt (34 mg, 0.25 mmol) followed by EDCI (48 mg, 0.25 mmol). Thesolution was stirred for 30 minutes, then treated with(trans)-4-aminocyclohexanol (29 mg, 0.25 mmol) followed by triethylamine(35 μL, 0.25 mmol). After stirring at ambient temperature for 5 hours,the reaction mixture was diluted with EtOAc, washed with saturated NH₄Cl(20 mL), saturated NaHCO₃, and brine, then dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by silica chromatography(4% MeOH/CH₂Cl₂) to yield the final product as white solid (23 mg, 60%).LCMS (apci) m/z=455.1 (M+H).

Example 141

(R)-tert-butyl3-(5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)propylcarbamate

To a mixture of(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation K, 200 mg, 0.560 mmol) and HATU (255 mg, 0.672 mmol)in DMF (2 mL) was added DIEA (292 μL, 1.68 mmol), followed by dropwiseaddition of tert-butyl 3-aminopropylcarbamate (117 mg, 0.672 mmol) atambient temperature. After stirring for 3 hours, the reaction wasdirectly purified by reverse-phase chromatography (5 to 70%acetonitrile/water) to yield the final product as white solid (250 mg,87%). LCMS (apci) m/z=414.1 (M+H-Boc).

Example 142

(R)—N-(3-aminopropyl)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of (R)-tert-butyl3-(5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)propylcarbamate(Example 141, 70 mg, 0.14 mmol) and HCl (4 N dioxane, 1.7 mL, 6.8 mmol)in a pressure reaction tube was heated at 85° C. for 12 hours thenconcentrated under reduced pressure. The crude material was purified byreverse-phase chromatography (5 to 40% acetonitrile/water) to yield thefinal product as white solid. LCMS (apci) m/z=400.1 (M+H).

Example 143

N—((S)-2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation ofN—(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-f(R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.Prepared according to the method described in Example 140, replacing(trans)-4-aminocyclohexanol with(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine LCMS (apci) m/z=471.0(M+H-Boc).

Step B: Preparation ofN—((S)-2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.To a solution ofN—(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(36 mg, 0.077 mmol) in THF (2 mL) was added HCl (3 N aq.) at ambienttemperature. The resulting mixture was stirred for 5 hours. The reactionwas diluted with EtOAc, washed with saturated NH₄Cl and brine, thendried (MgSO₄), filtered and concentrated. The crude material was rinsedwith ether to yield the final product as white solid (30 mg, 91%). LCMS(apci) m/z=431.1 (M+H).

Example 144

N—((S)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of (S)-1-amino-3-chloropropan-2-ol hydrochloride. Toa solution of benzaldehyde (4.50 g, 42.4 mmol) in EtOH (12 mL) was addedaqueous ammonia (4.01 g, 65.9 mmol) in several portions. After stirringfor 10 minutes, (S)-2-(chloromethyl)oxirane (3.81 g, 41.2 mmol) wasadded and the reaction mixture was stirred for 2 hours at ambienttemperature. The reaction mixture was then heated at 35-40° C. with aheating mantle for 6 hours, followed by stirring at ambient temperaturefor 18 hours. The reaction was concentrated to 5 mL and toluene (5 mL)was added. The mixture was heated to 36° C. and a solution ofconcentrated HCl (6.09 g, 61.8 mmol) and water (5.9 mL) was added slowlyover 5 minutes to maintain an internal reaction temperature range of36-41° C. The biphasic mixture was heated at 42-45° C. for 3 hours. Theorganic phase was separated and washed with water (10 mL). The aqueousphases were combined and ethanol (10 mL) was added. The mixture wasconcentrated to 10 mL, and ethanol (6×10 mL) was added, concentratingafter each addition. After the last concentration step, the slurry waswarmed to reflux, cooled to ambient temperature, and then placed at −20°C. for 18 hours. The product was collected by vacuum filtration, washedwith cold ethanol, and vacuum-dried, to provide the product as whitesolid (3.58 g, 60% yield).

Step B: Preparation ofN—((S)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.Prepared by the method described in Example 139, replacing azetidin-3-olhydrochloride with (S)-1-amino-3-chloropropan-2-ol hydrochloride. LCMS(apci) m/z=449.0 (M+H)

Example 145

N—((R)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of (R)-1-amino-3-chloropropan-2-ol hydrochloride.Prepared by the method described in Example 144, Step A, replacing(S)-2-(chloromethyl)oxirane with (R)-2-(chloromethyl)oxirane.

Step B: Preparation ofN—((R)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.Prepared by the method described in Example 139, replacing azetidin-3-olhydrochloride with (R)-1-amino-3-chloropropan-2-ol hydrochloride. LCMS(apci) m/z=449.0 (M+H)

Example 146

(R)—N-(2-chloroethoxy)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of 2-(2-chloroethoxyl)isoindoline-1,3-dione. A 1 Lround-bottomed flask was charged 2-hydroxyisoindoline-1,3-dione (16.6 g,98.71 mmol), followed by DMF (100 mL), then 1-bromo-2-chloroethane (25.2mL, 296.1 mmol), and then triethylamine (42.1 mL, 296.1 mmol). Afterstirring at ambient temperature overnight, the reaction mixture wasfiltered (GF/F) and rinsed with DMF. The filtrate (250 mL) was pouredinto ice-water (2 L) while stirring, and the resulting precipitate wasfiltered, rinsed with water, and dried, yielding the crude product as awhite solid (21 g). The crude product was triturated with heptane (3×400mL), filtered and air-dried, giving the product as white solid (17.6 g,79%).

Step B: Preparation of O-(2-chloroethyl)hydroxylamine hydrochloride. A 1L three-necked round-bottomed flask was charged HCl (6 M aq., 295 mL,1773 mmol), followed by 2-(2-chloroethoxyl)isoindoline-1,3-dione (10 g,44.3 mmol) with stirring. A water condenser was attached and thereaction was refluxed at 100° C. for 2 hours, then stirred at ambienttemperature overnight. The reaction mixture was filtered. Absolute EtOHwas added to the filtrate and filtrate was concentrated. The crudematerial was triturated from hot EtOH to yield the first crop of productas white solid (2.2 g). The mother liquor was concentrated andtriturated as described, yielding a second crop of product (1.7) g.

Step C: Preparation of(R)—N-(2-chloroethoxy)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.Prepared by the method described in Example 139, replacing azetidin-3-olhydrochloride with O-(2-chloroethyl)hydroxylamine hydrochloride. LCMS(apci) m/z=434.9 (M+H)

The compounds listed in Table B were prepared according to the methoddescribed in Example 139 or Example 140, by reacting(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation K) with an appropriate amine starting material in thepresence of an amide coupling reagent (e.g. HATU, EDCI/HOBt) and anorganic base (e.g. DIEA, TEA) in an appropriate solvent (e.g. DMF, DCM).

TABLE B Ex. # Structure Chemical Name Data 147

(R)-(5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3- yl)(3-hydroxy-3-methylazetidin-1-yl)methanone LCMS (apci) m/z = 427.1 (M + H) 148

(R)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-1- yl)-N-(3-hydroxypropyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z =415.1 (M + H) 149

N-(2,3-dihydroxypropyl)-5-((R)- 2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 431.1 (M + H) 150

N-((R)-2,3-dihydroxypropyl)-5- ((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide LCMS (apci) m/z = 431.0 (M + H) 151

(R)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-1- yl)-N-(4-hydroxybutyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z =429.1 (M + H) 152

(R)-N-(2-tert-butoxyethoxy)-5-(2- (5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 473.0 (M + H) 153

(R)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-1-yl)-N-methylpyrazolo[1,5- a]pyrimidine-3-carboxamide MS (apci) m/z =371.1 (M + H) 154

5-((R)-2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-1-yl)-N-((1S,3S)-3- hydroxycyclopentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 441.1 (M + H) 155

(R)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-1- yl)-N-(2-hydroxyethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide MS (apci) m/z =401.1 (M + H) 156

5-((R)-2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-1- yl)-N-((S)-2-hydroxypropyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide MS (apci) m/z =415.1 (M + H) 157

5-((R)-2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-1- yl)-N-((R)-2-hydroxypropyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide MS (apci) m/z =415.1 (M + H) 158

(R)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(2-hydroxy-2- methylpropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 429.1 (M + H) 159

(R)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-1- yl)-N-(1-(2-hydroxyethyl)piperidin-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide MS(apci) m/z = 484.2 (M + H) 160

(R)-N-(1,3-dihydroxypropan-2- yl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 431.1 (M + H) 161

(R)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(6-oxo-1,6-dihydropyridin- 3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 450.0 (M + H) 162

(R)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-1- yl)-N-(1-(methylsulfonyl)piperidin-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamideMS (apci) m/z = 518.1 (M + H) 163

(R)-N-(2-chloroethyl)-5-(2-(5- fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 419.1 (M + H) 164

(R)-N-(2-bromoethoxy)-5-(2-(5- fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 479.0 (M + H)

The compounds listed Table C were prepared by the method described inExamples 1, 139 or 140, by reacting(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation C) with an appropriate amine starting material in thepresence of an amide coupling reagent (e.g. HATU, EDCI/HOBt) and anorganic base (e.g. DIEA, TEA) in an appropriate solvent (e.g. DMF, DCM).

TABLE C Ex. # Structure Chemical Name Data 165

5-(2-(2,5-difluorophenyl)pyrrolidin- 1-yl)-N-(2-hydroxyethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z =388.1 (M + H) 166

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N-(2-hydroxypropyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 402.1 (M + H) 167

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N-(2-hydroxypropyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 402.1 (M + H) 168

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N- (3-hydroxy-2,2-dimethylpropyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z= 430.2 (M + H) 169

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N- ((1S,3S)-3-hydroxycyclopentyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 428.1 (M + H) 170

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N-(2-(4-hydroxypiperidin-1- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide LCMS (apci) m/z = 471.2 (M + H) 171

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N-(2-(4-methylpiperazin-1- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide LCMS (apci) m/z = 470.2 (M + H) 172

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N-(2-methoxyethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z= 402.1 (M + H) 173

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N-(1,3-dihydroxypropan-2- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide LCMS(apci) m/z = 418.1 (M + H) 174

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N-((2S,3R)-1,3-dihydroxybutan-2- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide LCMS (apci) m/z = 432.1 (M + H) 175

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N-((2S,3S)-1,3-dihydroxybutan-2- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide LCMS (apci) m/z = 432.1 (M + H) 176

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N-((2R,3S)-1,3-dihydroxybutan-2- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide LCMS (apci) m/z = 432.1 (M + H) 177

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N-((S)-1-hydroxypropan-2- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide LCMS(apci) m/z = 402.1 (M + H) 178

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N- ((S)-1-hydroxybutan-2-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide LCMS (apci) m/z = 416.1 (M +H) 179

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N-((S)-1-hydroxy-3-methylbutan-2- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide LCMS (apci) m/z = 430.1 (M + H) 180

5-((R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl)-N-((S)-1-hydroxy-3,3-dimethylbutan- 2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide LCMS (apci) m/z = 444.2 (M + H)

Example 181

N-cyclopropyl-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of(R)-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation O, 50 mg, 0.15 mmol) in DCM (2 mL) was added HOBt (40mg, 0.29 mmol) followed by EDCI (84 mg, 0.44 mmol). The solution wasstirred at ambient temperature for 15 minutes, then treated withtriethylamine (61 μL, 0.44 mmol) followed by cyclopropylamine (31 μL,0.44 mmol). After stirring for 16 hours the mixture was partitionedbetween saturated NH₄Cl solution (20 mL) and DCM (20 mL) and the aqueouslayer was extracted with DCM (2×10 mL). The combined organic phases werewashed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by silica gel column chromatography, elutingwith 2-4% MeOH/DCM, to afford the title product as white solid (44 mg,79%). MS (apci) m/z=381.1 (M+H).

Example 182

N-cyclopropyl-5-(2-(2-ethyl-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared according to the method of Example 181, substituting(R)-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid with(R)-5-(2-(2-ethyl-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation Q). MS (apci) m/z=395.1 (M+H).

The compounds listed in Table D were prepared by the method described inExample 181 or 182, by reacting(R)-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation O) or(R)-5-(2-(2-ethyl-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation Q) with an appropriate amine starting material in thepresence of an amide coupling reagent (e.g. EDCI/HOBt) and an organicbase (e.g. TEA) in an appropriate solvent (e.g. DCM).

TABLE D Ex. # Structure Chemical Name Data 183

(R)-N-tert-butyl-5-(2-(5-fluoro-2- methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide LCMS (apci) m/z = 397.1 (M +H) 184

(R)-5-(2-(5-fluoro-2-methylpyridin- 3-yl)pyrrolidin-1-yl)-N-isopropylpyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z =383.1 (M + H) 185

(R)-N-cyclobutyl-5-(2-(5-fluoro-2- methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide LCMS (apci) m/z = 395.1 (M +H) 186

(R)-5-(2-(5-fluoro-2-methylpyridin- 3-yl)pyrrolidin-1-yl)-N-methylpyrazolo[1,5-a]pyrimidine-3- carboxamide LCMS (apci) m/z = 355.1(M + H) 187

(R)-5-(2-(5-fluoro-2-methylpyridin- 3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide LCMS (apci) m/z = 341.0 (M + H) 188

(R)-5-(2-(5-fluoro-2-methylpyridin- 3-yl)pyrrolidin-1-yl)-N-(2-hydroxyethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z =385.1 (M + H) 189

(R)-5-(2-(5-fluoro-2-methylpyridin- 3-yl)pyrrolidin-1-yl)-N-((R)-2-hydroxypropyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z =399.1 (M + H) 190

(R)-5-(2-(5-fluoro-2-methylpyridin- 3-yl)pyrrolidin-1-yl)-N-(1-methylcyclopropyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 395.1 (M + H) 191

(R)-5-(2-(5-fluoro-2-methylpyridin- 3-yl)pyrrolidin-1-yl)-N-(2-methoxyethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z =399.1 (M + H) 192

(R)-(5-(2-(5-fluoro-2- methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3- yl)(3-hydroxyazetidin-1- yl)methanoneLCMS (apci) m/z = 397.1 (M + H) 193

(R)-5-(2-(5-fluoro-2-methylpyridin- 3-yl)pyrrolidin-1-yl)-N-(1-(hydroxymethyl)cyclopropyl) pyrazolo[1,5-a]pyrimidine-3- carboxamideLCMS (apci) m/z = 411.1 (M + H) 194

5-((R)-2-(5-fluoro-2-methylpyridin- 3-yl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 439.1 (M + H) 195

5-((R)-2-(5-fluoro-2-methylpyridin- 3-yl)pyrrolidin-1-yl)-N-((cis)-4-hydroxycyclohexyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 439.2 (M + H) 196

5-((R)-2-(5-fluoro-2-methylpyridin- 3-yl)pyrrolidin-1-yl)-N-((1S,3S)-3-hydroxycyclopentyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 425.1 (M + H) 197

5-((R)-2-(5-fluoro-2-methylpyridin- 3-yl)pyrrolidin-1-yl)-N-((1R,2R)-2-hydroxycyclopentyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 425.1 (M + H) 198

5-((R)-2-(5-fluoro-2-methylpyridin- 3-yl)pyrrolidin-1-yl)-N-((R)-quinuclidin-3-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 450.2 (M + H) 199

5-((R)-2-(2-ethyl-5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 453.2 (M + H) 200

5-((R)-2-(2-ethyl-5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-((1S,3S)-3-hydroxycyclopentyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci)m/z = 439.1 (M + H) 201

(R)-5-(2-(2-ethyl-5-fluoropyridin-3- yl)pyrrolidin-1-yl)-N-(2-hydroxy-2-methylpropyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS (apci) m/z =427.1 (M + H)

Example 202

(R)—N-tert-butyl-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A pressure flask was charged with(R)—N-tert-butyl-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Example 80, 10 mg, 0.024 mmol), dioxane (0.7 mL) and 2M HCl (0.100 mL,0.200 mmol). The flask was sealed and the reaction mixture was stirredat 80° C. for 5 days. The mixture was cooled to ambient temperature andconcentrated. The residue was purified by reverse-phase columnchromatography (0-50% acetonitrile/water) to afford the title compound(8.2 mg, 85%). MS (apci) m/z=399.1 (M+H).

Example 203

(R)—N-(2-chloroethyl)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 202, replacing(R)—N-tert-butyl-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamidewith(R)—N-(2-chloroethyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Example 163, 100 mg, 0.239 mmol), replacing 2 M HCl with 4 M HCldioxane solution, and reaction was conducted at 100° C. for 90 minutes.LCMS (apci) m/z=405.0 (M+H).

Example 204

N-cyclopropyl-5-((2R)-2-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of ethyl5-((2R)-2-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.A mixture of (R)-ethyl5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(Example 86, Step C, 140 mg, 0.378 mmol),4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (114 mg, 0.756 mmol),potassium carbonate (261 mg, 1.89 mmol) and sodium bromide (77.8 mg,0.756 mmol) in dry DMF (5 mL) was heated at 100° C. for 14 days. Themixture was concentrated and the residue purified by chromatography toafford the title compound (45 mg, 25% yield). MS (apci) m/z=485.0 (M+H).

Step B: Preparation of5-((2R)-2-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. The compound was prepared according to the method of Example 86,Step E, using ethyl5-((2R)-2-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(47 mg, 100%). MS (apci) m/z=457.0 (M+H).

Step C: Preparation ofN-cyclopropyl-5-((2R)-2-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.Prepared according to the method of Example 86, Step F, using5-((2R)-2-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid and cyclopropyl amine to yield the title compound as a white solid(33.0 mg, 99% yield.). MS (apci) m/z=496.1 (M+H).

Example 205

5-((2R)-2-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared according to the procedure described in Example 204 usingammonium chloride in place of cyclopropyl amine in Step C (white solid,13 mg, 85% yield.). MS (apci) m/z=456.0 (M+H).

Example 206

N-cyclopropyl-5-((2R)-2-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared according to the method of Example 204 using (R)-ethyl5-(2-(3-fluoro-5-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(Example 76, Step C) in Step A (36 mg, 82% yield). MS (apci) m/z=496.1(M+H).

Example 207

5-((2R)-2-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared according to the method of Example 204, using (R)-ethyl5-(2-(3-fluoro-5-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(Example 76, Step C) in Step A and ammonium chloride in Step C to yieldthe title compound as a white solid (19 mg, 55% yield.). MS (apci)m/z=456.0 (M+H).

Example 208

N-cyclopropyl-5-((2R)-2-(3-(2,3-dihydroxypropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution ofN-cyclopropyl-5-((2R)-2-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Example 206, 30 mg, 0.061 mmol) in dioxane (0.5 mL) was charged withtwo drops of 6N HCl and shaken for two minutes. DIEA (5 drops) was addedand the mixture directly purified by reverse phase column chromatography(0-50% acetonitrile/water) to affordN-cyclopropyl-5-((2R)-2-(3-(2,3-dihydroxypropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(23 mg, 83% yield) as a clear film. MS (apci) m/z=456.1 (M+H).

Example 209

5-((2R)-2-(3-(2,3-dihydroxypropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared from5-((2R)-2-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Example 207) according to the procedure of Example 208 (8.5 mg, 55%yield). MS (apci) m/z=416.0 (M+H).

Example 210

N-cyclopropyl-5-((2R)-2-(2-(2,3-dihydroxypropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared fromN-cyclopropyl-5-((2R)-2-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Example 204) using the procedure of Example 208 (19 mg, 65% yield). MS(apci) m/z=456.1 (M+H).

Example 211

5-((2R)-2-(2-(2,3-dihydroxypropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared from5-((2R)-2-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Example 205) using the procedure of Example 208 (10 mg, 95% yield). MS(apci) m/z=416.0 (M+H).

Example 212

5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)-N—((R)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of (S)-ethyl2-(tert-butoxycarbonylamino)-5-(5-fluoropyridin-3-yl)-5-oxopentanoate. Asolution of 3-bromo-5-fluoropyridine (4.28 g, 24.3 mmol) in dry THF (25mL) was cooled to −40 to −50° C. and 2M isopropylmagnesium chloride inTHF (10.2 mL, 20.4 mmol) was added. The mixture was allowed to warm to0° C. and was stirred for 30 minutes. The mixture was cooled to −20° C.and a solution of (S)-1-tert-butyl 2-ethyl5-oxopyrrolidine-1,2-dicarboxylate (5.00 g, 19.4 mmol) in dry THF (15mL) was added. The mixture was allowed to reach ambient temperature over30 minutes and was stirred at ambient temperature for 30 minutes. Thereaction was slowly quenched with 2M HCl (10 mL, 20.0 mmol) followed by10% aqueous NH₄Cl (10 mL). The mixture was stirred for 10 minutes andwas transferred to a separatory funnel using MTBE rinses (10 mL).Heptane (15 mL) was added and the organic layer was removed. The organiclayer was washed 10% aqueous NH₄Cl (25 mL) and DI H₂O (25 mL). Theorganic layer was concentrated to provide the crude product as a yellowoil (7.03 g, 102%).

Step B: Preparation of (2S,5R)-ethyl5-(5-fluoropyridin-3-yl)pyrrolidine-2-carboxylate. (S)-ethyl2-(tert-butoxycarbonylamino)-5-(5-fluoropyridin-3-yl)-5-oxopentanoate(4.80 g, 13.55 mmol) was treated with TFA (24 mL) and the mixture wasstirred at ambient temperature for 45 minutes. The mixture wasconcentrated and the residue was dissolved in H₂O (10 mL) and EtOAc (50mL) was added. The mixture was treated slowly with saturated aqueousK₂CO₃ (15 mL). The aqueous layer was separated and the organic layer waswashed with 10% aqueous NH₄Cl. The EtOAc layer was concentrated to givecrude (S)-ethyl5-(5-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrole-2-carboxylate as anamber oil (2.67 g, 83% yield). The oil was dissolved in isopropylalcohol (20 mL) and was treated with 10% Pd/C (0.266 g, 0.250 mmol). Thereaction vessel was purged with hydrogen gas (3×) and mixture wasstirred at ambient temperature under 1 atm of hydrogen for 16 hours. Thereaction was purged with nitrogen and filtered through a Celite pad. Thefiltrate was concentrated to furnish the title compound as an amber oilthat began to solidify upon standing (2.58 g, 96%).

Step C: Preparation of((2S,5R)-5-(5-fluoropyridin-3-yl)pyrrolidin-2-yl)methanol. To a solutionof (2S,5R)-ethyl 5-(5-fluoropyridin-3-yl)pyrrolidine-2-carboxylate (1.10g, 4.62 mmol) in dry THF (20 mL) was added 2M LiAlH₄ in THF (3.00 mL,6.00 mmol). The reaction was stirred at ambient temperature for 30minutes and Na₂SO₄ 10 H₂O (3.00 g, 9.31 mmol) was added in smallportions. The mixture was stirred for 3 hours at ambient temperature andwas filtered. The collected solid was washed with EtOAc and the washescombined with the filtrate. The solution was concentrated to providecrude ((2S,5R)-5-(5-fluoropyridin-3-yl)pyrrolidin-2-yl)methanol (0.95 g,105% yield) that was used directly in the next step. MS (apci) m/z=197.1(M+H).

Step D: Preparation of ethyl5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.A mixture of ((2S,5R)-5-(5-fluoropyridin-3-yl)pyrrolidin-2-yl)methanol(0.910 g, 4.64 mmol), ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 1.05 g,4.64 mmol) and DIEA (1.10 mL, 6.00 mmol) in isopropyl alcohol (1.0 mL)was heated at 90° C. for 16 hours. The reaction mixture was concentratedand the residue was purified by reverse phase column chromatography(0-50% acetonitrile/water) followed by normal phase columnchromatography (2-5% MeOH/DCM) to afford ethyl5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(0.250 g, 14% yield) as a viscous, clear oil. MS (apci) m/z=386.0 (M+H).

Step E: Preparation of5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. A mixture of ethyl5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(0.250 g, 0.649 mmol) and 2M sodium hydroxide (3.24 mL, 6.48 mmol) inMeOH (10 mL) was stirred at ambient temperature for 4 days followed by50° C. for 5 hours. The reaction was cooled to ambient temperature and4M HCl in dioxane (1.78 mL, 7.14 mmol) was added. The mixture wasconcentrated and the residue was purified by reverse phase columnchromatography (0-40% acetonitrile/water) to afford5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (210 mg, 90% yield) as a white solid. MS (apci) m/z=358.0 (M+H).

Step F: Preparation of5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)-N—((R)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.To a mixture of5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (10.0 mg, 0.028 mmol), (R)-1,1,1-trifluoropropan-2-amine (6.33 mg,0.056 mmol) and HATU (10.5 mg, 0.045 mmol) in dry DMF (0.2 mL) was addedDIEA (15.0 μL, 0.084 mmol). The reaction vessel was flushed withnitrogen, sealed, and the reaction stirred at ambient temperature for 16hours. The reaction mixture was directly purified by reverse phasecolumn chromatography (0-50% CH₃CN/H₂O) to provide the title compound(6.50 mg, 51% yield) as a white solid. MS (apci) m/z=453.0 (M+H).

Example 213

5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)-N—((S)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared according to the method of Example 212, Step F, using(S)-1,1,1-trifluoropropan-2-amine (white solid; 5.5 mg, 43%). MS (apci)m/z=453.0 (M+H).

Example 214

5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared according to the method of Example 212, Step F, using1-methylcyclopropane amine (white solid; 2.5 mg, 22%). MS (apci)m/z=411.1 (M+H).

Example 215

5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)-N-isopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared according to the method of Example 212, Step F, using isopropylamine (white solid; 2.5 mg, 12%). MS (apci) m/z=399.1 (M+H).

Example 216

5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)-N—((S)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of (ethyl5-((2R,4S)-4-acetoxy-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.To a mixture of ethyl5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(Example 41, Step E, 260 mg, 0.702 mmol) and PPh₃ (460 mg, 1.75 mmol) inTHF (10.0 mL) was added DIAD (276 μL, 1.40 mmol) followed by acetic acid(80.4 μL, 1.40 mmol). The reaction was stirred at ambient temperaturefor 48 hours and then concentrated. The residue was purified by reversephase column chromatography (0-70% acetonitrile/water) to afford ethyl5-((2R,4S)-4-acetoxy-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(228 mg, 79% yield). MS (apci) m/z=413.0 (M+H).

Step B: Preparation of5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. A mixture of ethyl5-((2R,4S)-4-acetoxy-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(225 mg, 0.546 mmol) and NaOH (131 mg, 1.64 mmol) in MeOH (1.0 mL) wasstirred at ambient temperature for 60 hours followed by 3 hours at 60°C. The mixture was cooled to ambient temperature and 4M HCl in dioxane(1 mL) was added. The mixture was concentrated and the residue wastreated with DCM. The mixture was filtered through Celite andconcentrated to afford5((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (188 mg, 10% yield) as a white solid. MS (apci) m/z=343.0 (M+H).

Step C: Preparation of5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)-N—((S)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.Prepared according to the method of Example 212, Step F, using5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid and (S)-1,1,1-trifluoropropan-2-amine (white solid; 2.1 mg, 16%yield). MS (apci) m/z=438.0 (M+H).

Example 217

5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)-N-isopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared according to the method of Example 212, Step F, using5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Example 216, Step B) and isopropyl amine. The titlecompound was obtained as a white solid (5.5 mg, 49% yield). MS (apci)m/z=384.1 (M+H).

Example 218

5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)-N-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared according to the method of Example 212, Step F, using5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Example 216, Step B) and methyl amine. The title compoundwas obtained as a white solid (6.1 mg, 29% yield). MS (apci) m/z=356.1(M+H).

Example 219

5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)-N-isopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: Preparation of (2S,5R)-1-tert-butyl 2-ethyl5-(5-fluoropyridin-3-yl)pyrrolidine-1,2-dicarboxylate. A mixture of(2S,5R)-ethyl 5-(5-fluoropyridin-3-yl)pyrrolidine-2-carboxylate (Example212, Step B, 1.00 g, 4.20 mmol), di-tert-butyl dicarbonate (0.962 g,4.41 mmol) and PS-DMAP (0.210 g, 0.210 mmol, 1.00 mmol/g load) in dryDCM (20 mL) was mixed at ambient temperature for 18 hours. The reactionmixture was filtered and the filtrate was concentrated. The residue waspurified on a silica gel column (2-10% MeOH/DCM) to afford(2S,5R)-1-tert-butyl 2-ethyl5-(5-fluoropyridin-3-yl)pyrrolidine-1,2-dicarboxylate (1.36 g, 96%yield) as a yellow oil. MS (apci) m/z=339.0 (M+H).

Step B: Preparation of (2S,5R)-1-tert-butyl 2-ethyl5-(5-fluoropyridin-3-yl)-2-methylpyrrolidine-1,2-dicarboxylate. Asolution of (2S,5R)-1-tert-butyl 2-ethyl5-(5-fluoropyridin-3-yl)pyrrolidine-1,2-dicarboxylate (250 mg, 0.739mmol) in THF (10 mL) was cooled to −78° C. and 0.5 M KHMDS in toluene(1.77 mL, 0.885 mmol) was added dropwise. The reaction was stirred for 1hour at −78° C. and MeI (59.9 μL, 0.960 mmol) was added. The reactionwas allowed to warm to ambient temperature and saturated aqueous NaCl(20 mL) was added. The mixture was extracted with EtOAc (2×50 mL) andthe combined organic extracts were filtered and concentrated to afford(2S,5R)-1-tert-butyl 2-ethyl5-(5-fluoropyridin-3-yl)-2-methylpyrrolidine-1,2-dicarboxylate (255 mg,98% yield) as a clear oil. MS (apci) m/z=353.1 (M+H).

Step C: Preparation of (2S,5R)-tert-butyl5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate.A solution of (2S,5R)-1-tert-butyl 2-ethyl5-(5-fluoropyridin-3-yl)-2-methylpyrrolidine-1,2-dicarboxylate (240 mg,0.681 mmol) in THF (10 mL) was cooled to −78° C. and 1M LiAlH₄ in THF(1.50 mL, 1.50 mmol) was added dropwise. The reaction was allowed towarm to 0° C. and was quenched with small portions of Na₂SO₄-10H₂O (967mg, 6.81 mmol). The mixture was filtered and concentrated to afford(2S,5R)-tert-butyl5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate(200 mg, 95% yield). MS (apci) m/z=311.1 (M+H).

Step D: Preparation of((2S,5R)-5-(5-fluoropyridin-3-yl)-2-methylpyrrolidin-2-yl)methanolhydrochloride. To a solution of (2S,5R)-tert-butyl5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate(200 mg, 0.644 mmol) in DCM (5 mL) was added 4M HCl in dioxane (1.61 mL,6.44 mmol). The reaction was stirred at ambient temperature for 16 hoursand then concentrated to afford((2S,5R)-5-(5-fluoropyridin-3-yl)-2-methylpyrrolidin-2-yl)methanolhydrochloride (130 mg, 96% yield). MS (apci) m/z=211.1 (M+H).

Step E: Preparation of ethyl5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.A sealed reaction vessel was charged with((2S,5R)-5-(5-fluoropyridin-3-yl)-2-methylpyrrolidin-2-yl)methanolhydrochloride (0.135 g, 0.547 mmol), ethyl5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 0.136 g,0.602 mmol), DIEA (0.124 mL, 0.711 mmol) and isopropyl alcohol (1 mL).The vessel was sealed and the mixture was heated at 190° C. for 48hours. The reaction was cooled to ambient temperature and concentrated.The residue was purified by reverse phase column chromatography (0-50%acetonitrile/water) to afford ethyl5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(55 mg, 25% yield) as a viscous clear oil. MS (apci) m/z=400.1 (M+H).

Step F: Preparation of5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. A mixture of ethyl5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(52.0 mg, 0.130 mmol) and NaOH (26.0 mg, 0.325 mmol) in MeOH (1.0 mL)was stirred at ambient temperature for 60 hours. The reaction wastreated with HCl (4 N dioxane, 163 μL, 0.651 mmol) and concentrated. Theresidue was treated with DCM and filtered through Celite. The solutionwas concentrated to afford5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (29 mg, 60% yield) as a white solid. MS (apci) m/z=372.0 (M+H).

Step G: Preparation of5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)-N-isopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide.Prepared according to the method of Example 212, Step F, using5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid and isopropyl amine. The title compound was obtained as a whitesolid (7.2 mg, 46% yield). MS (apci) m/z=413.1 (M+H).

Example 220

5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)-N—((S)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared according to the method of Example 212, Step F, using5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Example 219, Step F) and (S)-1,1,1-trifluoropropan-2-amine. Thetitle compound was obtained as a white solid (5.4 mg, 31% yield). MS(apci) m/z=467.1 (M+H).

Example 221

(R)-(5-(2-(2-amino-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(azetidin-1-yl)methanone

A mixture of(R)—N-(3-aminopropyl)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamidehydrochloride (Example 142, 83 mg, 0.190 mmol) and POCl₃ (697 μL, 7.62mmol) was sealed and heated at 100° C. for 5 minutes. The reactionmixture was diluted with 1 mL heptane and azeotroped twice to yield thecrude product. The crude material was purified by reverse-phasechromatography (5 to 40% acetonitrile/water) to yield the title productas white solid (2 mg, 3%). LCMS (apci) m/z=382.3 (M+H).

Example 222

(R)-tert-butyl3-(5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)propylcarbamate

Step A: Preparation of (R)-tert-butyl2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidine-1-carboxylate: A solutionof tert-butyl pyrrolidine-1-carboxylate (1 mL 5.70 mmol) and(−)-sparteine (1.31 mL, 5.70 mmol) in anhydrous MTBE (30 mL) was firstcooled to −78° C. under nitrogen, followed by addition of sec-butyllithium (4.07 mL, 1.4M, 5.70 mmol) drop-wise over 15 minutes with asyringe, maintaining the temperature below −75° C. The pale yellowishsolution was stirred at −78° C. for 3 hours before being treated withzinc chloride (3.80 mL, 1.0 M, 3.80 mmol) dropwise over 15 minutes whilemaintaining the temperature below −73° C. The mixture was stirred at−78° C. for 30 minutes, then placed into an ambient temperature waterbath and stirred for another hour. At this point a large amount of whiteprecipitate was present. The mixture was treated with3-bromo-2-chloro-5-fluoropyridine (1.00 g, 4.75 mmol) in MTBE (5 mL),followed by addition of palladium acetate (53 mg, 0.24 mmol) andtri-t-butylphosphine tetrafluoroborate (83 mg, 0.28 mmol). The mixturewas allowed to stir at ambient temperature overnight to reachcompletion. The mixture was treated with NH₄OH (1 mL), stirred for 30minutes and filtered through GF/F paper, washing with MTBE. The filtratewas washed with 10% citric acid (30 mL) and the aqueous layer wasback-washed with MTBE (2×30 mL). The combined organic phases were washedwith brine (20 mL), dried (MgSO₄), and concentrated to afford the crudeproduct as dark yellowish oil. This crude material was purified on asilica 50 g Biotage SNAP cartridge eluting with 10% EtOAc in hexanes toafford the desired product as colorless oil (0.5 g, 35%). MS (apci pos)m/z=201.1 (M+H-Boc).

Step B: Preparation of (R)-2-chloro-5-fluoro-3-(pyrrolidin-2-yl)pyridinedihydrochloride: To a dioxane (5 mL) solution of (R)-tert-butyl2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidine-1-carboxylate (500 mg, 1.66mmol) was added HCl (4 N dioxane, 20 mL), followed by stirring atambient temperature overnight. The mixture was concentrated and treatedwith Et₂O, then vacuum-dried, to provide the product as a white solid(0.36 g, 80%). MS (apci pos) m/z=201.1 (M+H). The enantiomeric excess(ee %) of the product was determined to be >92% according to the methoddescribed in Preparation A.

Step C: Preparation of (R)-ethyl5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate:To a solution of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate(Preparation B, Step A, 275 mg, 1.33 mmol) in anhydrous DMF (5 mL) wasadded (Benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (BOP) (646 mg, 1.46 mmol). The heterogeneous mixturewas stirred for 10 minutes before adding DIEA (1.16 mL, 6.6 mmol),followed by addition of(R)-2-chloro-5-fluoro-3-(pyrrolidin-2-yl)pyridine dihydrochloride (363mg, 1.33 mmol). The reaction was stirred at ambient temperatureovernight to reach completion. The mixture was partitioned between 10%citric acid (30 mL) and EtOAc (30 mL), and the aqueous layer wasextracted with EtOAc (2×20 mL). The combined organic phases were washedsuccessively with water (20 mL), saturated NaHCO₃ (20 mL), water (20 mL)and brine (3×20 mL), then dried (Na₂SO₄) and concentrated to afford thecrude product as an orange foam. The crude material was purified on a 25g Biotage SNAP silica cartridge eluting with 1% MeOH/DCM to afford thedesired product as cream-colored foam (0.35 g, 68%). MS (apci pos)m/z=390.0 (M+H).

Step D: Preparation of(R)-5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. Prepared by the method described in Preparation C, Step B,replacing (R)-ethyl5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylatewith (R)-ethyl5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.MS (apci pos) m/z=361.9 (M+H).

Step E: Preparation of (R)-tert-butyl3-(5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)propylcarbamate.Prepared according to the method described in Example 141, replacing(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid with(R)-5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid to yield the title product as white solid. LCMS (apci pos)m/z=418.2 (M+H-Boc).

Example 223

(R)—N-(3-aminopropyl)-5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of (R)-tert-butyl3-(5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)propylcarbamate(Example 222, 6 mg, 0.012 mmol) and HCl (4 N dioxane, 145 μL, 0.58 mmol)was stirred at ambient temperature for 2 hours and concentrated to yieldthe product as white solid. LCMS (apci pos) m/z=418.1 (M+H).

Example 224

(R)—N-(2-tert-butoxyethoxy)-5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared according to the method described in Example 222, Step E,replacing tert-butyl 3-aminopropylcarbamate withO-(2-tert-butoxyethyl)hydroxylamine hydrochloride to yield the titleproduct as white solid (58 mg, 87%). LCMS (apci) m/z=476.9 (M+H).

Example 225

(R)-5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(2-hydroxyethoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)—N-(2-tert-butoxyethoxy)-5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Example 224, 57 mg, 0.120 mmol) was treated with HCl (4 N dioxane, 1.49mL, 5.98 mmol), followed by two drops of MeOH to make a clear colorlesssolution. After stirring 30 minutes at ambient temperature, the reactionwas concentrated and dried to yield the title product as white solid,assuming quantitative yield. LCMS (apci) m/z=421.0 (M+H)

Example 226

(R)—N-tert-butyl-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Prepared by the method described in Example 140, using(R)-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation R) and 2-methylpropan-2-amine. The residue waspurified by silica column chromatography, eluting with 3% MeOH/DCM toyield the title compound (26 mg, 75% yield). MS (apci) m/z=413.1 (M+H).

The compounds listed in the following Table were also prepared accordingto the method described in Example 140, by reacting(R)-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation R) with the appropriate amine starting material in thepresence of an amide coupling reagent (e.g. EDCI/HOBt), an organic base(for example, TEA) in a solvent (for example, DCM).

TABLE E Ex. # Structure Chemical Name Data 227

(R)-5-(2-(5-fluoro-1-methyl-2- oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N- isopropylpyrazolo[1,5- a]pyrimidine-3-carboxamideMS (apci) m/z = 399.1 (M + H) 228

(R)-N-cyclopropyl-5-(2-(5- fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 397.1 (M + H) 229

(R)-5-(2-(5-fluoro-1-methyl-2- oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-(6- methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 448.1 (M + H) 230

(R)-N-cyclobutyl-5-(2-(5-fluoro- 1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 411.1 (M + H) 231

(R)-5-(2-(5-fluoro-1-methyl-2- oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-(pyridin-3- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 434.1 (M + H) 232

(R)-N-(cyclopropylmethyl)-5-(2- (5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 411.1 (M + H) 233

5-((R)-2-(5-fluoro-1-methyl-2- oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-((S)-1- hydroxy-3,3-dimethylbutan-2-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide MS (apci) m/z = 457.1 (M +H) 234

5-((R)-2-(5-fluoro-1-methyl-2- oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-((1R,2R)-2- hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 455.1 (M + H) 235

N-((R)-1-cyclopropylethyl)-5- ((R)-2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 425.1 (M + H) 236

N-((S)-1-cyclopropylethyl)-5- ((R)-2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 425.1 (M + H) 237

(R)-5-(2-(5-fluoro-1-methyl-2- oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-(1- methylcyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 411.1 (M + H) 238

5-((R)-2-(5-fluoro-1-methyl-2- oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-((trans)-4- hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 455.1 (M + H) 239

(R)-5-(2-(5-fluoro-1-methyl-2- oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-(5- fluoropyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide MS (apci) m/z = 452.1 (M + H)

Example 240

(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a suspension of(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (Preparation K, 101 mg, 0.283 mmol) in THF (5 mL) was addedtriethylamine (34.3 mg, 0.339 mmol), followed by the addition of2,4,6-trichlorobenzoyl chloride (75.8 mg, 0.311 mmol). The suspensionwas stirred for 2 hours and then 3-methyl-1H-pyrazol-5-amine (35.7 mg,0.367 mmol) was introduced. The reaction was heated at 60° C. for 3hours. After cooling to room temperature, the reaction was partitionedbetween EtOAc (20 mL) and saturated aqueous NaHCO₃ (10 mL). Afterphase-separation, the aqueous layer was extracted with EtOAc (2×10 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The residue was purified via silica chromatography (EtOAc/MeOH 20:1) toyield the title product (23 mg, 19%). LCMS (apci) m/z=437.0 (M+H).

The compounds listed in Table F were also prepared according to themethod described in Example 240, using(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid, Preparation K) and an appropriate amine

TABLE F Ex. # Structure Chemical Name Data 241

(R)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(1-methyl-1H-pyrazol-3- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide LCMS (apci) m/z = 437.0 (M + H) 242

(R)-N-(3-cyclopropyl-1H-pyrazol- 5-yl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide LCMS (apci) m/z = 463.0 (M + H) 243

(R)-N-(3-ethyl-1H-pyrazol-5-yl)- 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide LCMS(apci) m/z = 451.0 (M + H) 244

(R)-5-(2-(5-fluoro-2- methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(1-isopropyl-1H-pyrazol-3- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide LCMS (apci) m/z = 465.0 (M + H)

The compounds in Table G can also be prepared according to the method ofExample 240.

TABLE G Ex. # Structure Name 245

(R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(2-methyl-1H- imidazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 246

(R)-N-(1,2-dimethyl-1H-imidazol-4- yl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide

What is claimed is:
 1. A method for treating one or more symptoms of acancer exhibiting one or more of overexpression, activation,amplification, and mutation of a Trk kinase in a mammal, which comprisesadministering to said mammal a therapeutically effective amount of acompound of formula I

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H or (1-6Calkyl); R² is H, (1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)difluoroalkyl,-(1-6C)trifluoroalkyl, -(1-6C)chloroalkyl, -(2-6C)chlorofluoroalkyl,-(2-6C)difluorochloroalkyl, -(2-6C)chlorohydroxyalkyl,-(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6Calkyl)SO₂NH₂, -(1-6C alkyl)NHSO₂(1-3C alkyl), -(1-6C alkyl)NH₂, -(1-6Calkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl)₂, -(1-6Calkyl)NHC(═O)O(1-4C alkyl), -(1-6C alkyl)hetCyc¹, -(1-6C alkyl)hetAr¹,hetAr², hetCyc², —O (1-6C alkyl) which is optionally substituted withhalogen, OH or (1-4C)alkoxy, —O(3-6C cycloalkyl), Cyc¹, -(1-6Calkyl)(3-6C cycloalkyl), -(1-6Calkyl)(1-4C alkoxy), -(1-6Chydroxyalkyl)(1-4C alkoxy), a bridged 7-membered cycloalkyl ringoptionally substituted with (1-6C)hydroxyalkyl, or a bridged 7-8membered heterocyclic ring having 1-2 ring nitrogen atoms; or NR¹R²forms a 4-6 membered azacyclic ring optionally substituted with one ormore substituents independently selected from (1-6C)alkyl, OH, CO₂H,(1-3C alkyl)CO₂H, —O(1-6C alkyl) and (1-6C)hydroxyalkyl; hetCyc¹ is a5-6 membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, wherein hetCyc¹ is optionally substituted withoxo, OH, halogen or (1-6C)alkyl; hetCyc² is a 6 membered carbon-linkedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O, wherein hetCyc² is optionally substituted with F, SO₂NH₂,SO₂(1-3C alkyl) or halogen; hetAr¹ is a 5-membered heteroaryl ringhaving 1-2 ring heteroatoms independently selected from N and O andoptionally substituted with (1-4C)alkyl; hetAr² is a 5-6 memberedheteroaryl ring having 1-2 ring nitrogen atoms and optionallysubstituted with one or more substituents independently selected from(1-4C)alkyl, (3-6C)cycloalkyl, halogen and OH; Cyc¹ is a 3-6 memberedcycloalkyl ring which is optionally substituted with one or moresubstituents independently selected from -(1-4C alkyl), —OH, —OMe,—CO₂H, -(1-4C alkyl)OH, halogen and CF₃; Y is (i) phenyl optionallysubstituted with one or more substituents independently selected fromhalogen, (1-4C)alkoxy, —CF₃—CHF₂, —O(1-4C alkyl)hetCyc³, -(1-4Calkyl)hetCyc³, —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl),or (ii) a 5-6 membered heteroaryl ring having a ring heteroatom selectedfrom N and S, wherein said heteroaryl ring is optionally substitutedwith one or more substituents independently selected from halogen,—O(1-4C alkyl), (1-4C)alkyl and NH₂, or (iii) a pyrid-2-on-3-yl ringoptionally substituted with one or more substituents independentlyselected from halogen and (1-4C)alkyl; hetCyc³ is a 5-6 memberedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O and optionally substituted with (1-6C)alkyl; X is —CH₂—,—CH₂CH₂—, —CH₂O— or —CH₂NR^(d)—; R^(d) is H or -(1-4C alkyl); R³ is H or-(1-4C alkyl); each R⁴ is independently selected from halogen,-(1-4C)alkyl, —OH, -(1-4C)alkoxy, —NH₂, —NH(1-4C alkyl) and —CH₂OH; andn is 0, 1, 2, 3, 4, 5 or 6; wherein said cancer is selected from thegroup consisting of neuroblastoma, ovarian cancer, colorectal cancer,pancreatic cancer, breast cancer, prostate cancer, lung cancer, coloncancer, stomach cancer, bladder cancer, uterine cancer, rectal cancer,thyroid cancer, and kidney cancer.
 2. The method of claim 1, wherein: R¹is H or -(1-6C alkyl); R² is H, -(1-6C)alkyl, -(1-6C)fluoroalkyl,-(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6Calkyl)SO₂NH₂, -(1-6C alkyl)NHSO₂(1-3C alkyl), -(1-6C alkyl)NH₂, -(1-6Calkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl)₂, -(1-6C alkyl)hetCyc¹,-(1-6C alkyl)hetAr¹, hetAr², hetCyc², —O(1-6C alkyl), —O(3-6Ccycloalkyl), Cyc¹, or a bridged 7-membered cycloalkyl ring, or NR¹R²forms a 4-6 membered azacyclic ring optionally substituted with one ormore substituents independently selected from -(1-6C)alkyl, —OH, —CO₂Hand -(1-3C alkyl)CO₂H; hetCyc¹ is a 5-6 membered heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O, whereinhetCyc¹ is optionally substituted with oxo; hetCyc² is a 6 memberedcarbon-linked heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, wherein hetCyc² is optionallysubstituted with F, SO₂NH₂, or SO₂(1-3C alkyl); hetAr¹ is a 5-memberedheteroaryl ring having 1-2 ring heteroatoms independently selected fromN and O and optionally substituted with -(1-4C)alkyl; hetAr² is a 5-6membered heteroaryl ring having 1-2 ring nitrogen atoms and optionallysubstituted with one or more substituents independently selected from-(1-4C)alkyl; Cyc¹ is 3-6 membered cycloalkyl ring which is optionallysubstituted with one or more substituents independently selected from-(1-4C alkyl), —OH, —OMe, —CO₂H and -(1-4C alkyl)OH; Y is (i) phenyloptionally substituted with one or more substituents independentlyselected from halogen, -(1-4C)alkoxy, —CF₃—CHF₂, —O(1-4C alkyl)hetCyc³and —O(1-4C alkyl)O(1-3C alkyl), or (ii) a 5-6 membered heteroaryl ringhaving a ring heteroatom selected from N and S, wherein said heteroarylring is optionally substituted with one or more substituentsindependently selected from halogen, —O(1-4C alkyl) and (1-4C)alkyl;hetCyc³ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O; X is —CH₂—, —CH₂CH₂—, —CH₂O— or—CH₂NR^(d)—; R^(d) is H or -(1-4C alkyl); R³ is H or -(1-4C alkyl); eachR⁴ is independently selected from halogen, -(1-4C)alkyl, —OH,-(1-4C)alkoxy, NH₂, NH(1-4C alkyl) and CH₂OH; and n is 0, 1, 2, 3, 4, 5or
 6. 3. The method of claim 1, wherein: R¹ is H or -(1-6C alkyl); andR² is H, -(1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl,-(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO₂NH₂, -(1-6Calkyl)NHSO₂(1-3C alkyl), -(1-6C alkyl)NH₂, -(1-6C alkyl)NH(1-4C alkyl),-(1-6C alkyl)N(1-4C alkyl)₂, -(1-6C alkyl)hetCyc¹, -(1-6C alkyl)hetAr¹,hetAr², —O(1-6C alkyl), —O(3-6C cycloalkyl), or a 3, 4 or 5 memberedcycloalkyl ring optionally substituted with one or more substituentsindependently selected from -(1-4C alkyl), —OH, —OMe, —CO₂H and -(1-4Calkyl)OH, or NR¹R² forms a 4-6 membered azacyclic ring optionallysubstituted with one or more substituents independently selected from-(1-6C)alkyl, —OH, —CO₂H and -(1-3C alkyl)CO₂H.
 4. The method of claim1, wherein: R¹ is H or -(1-6C alkyl); R² is H, -(1-6C)alkyl,-(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6Calkyl)CN, -(1-6C alkyl)SO₂NH₂, -(1-6C alkyl)NHSO₂(1-3C alkyl), -(1-6Calkyl)NH₂, -(1-6C alkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl)₂,-(1-6C alkyl)hetCyc¹, -(1-6C alkyl)hetAr¹, hetAr², hetCyc², —O(1-6Calkyl), —O(3-6C cycloalkyl), or a bridged 7-membered cycloalkyl ring, orNR¹R² forms a 4-6 membered azacyclic ring optionally substituted withone or more substituents independently selected from -(1-6C)alkyl, —OH,—CO₂H and -(1-3C alkyl)CO₂H.
 5. The method of claim 1, wherein R² is Hor -(1-6C)alkyl.
 6. The method of claim 5, wherein R² is methyl, ethyl,isopropyl or tert-butyl.
 7. The method of claim 5, wherein R² is H. 8.The method of claim 1, wherein R² is -(1-6C)hydroxyalkyl or-(2-6C)dihydroxyalkyl.
 9. The method of claim 8, wherein R² is CH₂CH₂OH,CH₂CH(OH)CH₂OH or C(CH₃)(CH₂OH)₂.
 10. The method of claim 1, wherein R²is Cyc¹ or a bridged 7-membered cycloalkyl ring.
 11. The method of claim10, wherein R² is Cyc¹ optionally substituted with optionallysubstituted with one or two substituents independently selected frommethyl, —OH, —CH₂OH and —CO₂H.
 12. The method of claim 11, wherein R² iscyclopropyl.
 13. The method of claim 1, wherein Cyc¹ is a 3, 4 or 5membered cycloalkyl ring which is optionally substituted with one ormore substituents independently selected from -(1-4C alkyl), —OH, —OMe,—CO₂H, -(1-4C alkyl)OH, halogen and CF₃.
 14. The method of claim 1,wherein R² is cyclopropyl optionally substituted with one or moresubstituents independentlyselected from methyl, —CO₂H, or —CH₂OH. 15.The method of claim 1, wherein R² is —O(1-6C alkyl) or —O(3-6Ccycloalkyl).
 16. The method of claim 15, wherein R² is selected from—OMe, —OEt and cyclopropoxy.
 17. The method of claim 1, wherein R² isselected from -(1-6C)fluoroalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO₂NH₂,and -(1-6C alkyl)NHSO₂(1-3C alkyl).
 18. The method of claim 17, whereinR² is selected from —C(CH₃)₂CH₂F, —C(CH₃)₂CH₂OH, CH₂C(CH₃)₂OH, —CH₂CN,—C(CH₃)₂CN, —CH₂CH₂SO₂NH₂, —CH₂CH₂NHSO₂CH₃ and —C(CH₃)₂CH₂NHSO₂CH₃. 19.The method of claim 1, wherein R² is selected from -(1-6C alkyl)NH₂,-(1-6C alkyl)NH(1-4C alkyl) and -(1-6C alkyl)N(1-4C alkyl)₂.
 20. Themethod of claim 1, wherein R² is selected from -(1-6C alkyl)hetCyc¹ and-(1-6C alkyl)hetAr¹.
 21. The method of claim 1, wherein R² is selectedfrom -(1-6C alkyl)hetAr¹ and hetAr².
 22. The method of claim 1, whereinR¹ is H.
 23. The method of claim 1, wherein NR¹R² forms a 4-6 memberedazacyclic ring optionally substituted with one or more substituentsindependently selected from -(1-6C)alkyl, —OH, —CO₂H and -(1-3Calkyl)CO₂H.
 24. The method of claim 1, wherein X is —CH₂— or —CH₂CH₂—.25. The method of claim 1, wherein X is —CH₂O— or —CH₂NR^(d)—.
 26. Themethod of claim 1, wherein Y is phenyl optionally substituted with oneor more substituents independently selected from halogen, -(1-4C)alkoxy,CF₃, CHF₂, —O(1-4C alkyl)hetCyc³, -(1-4C alkyl)hetCyc³ and —O(1-4Calkyl)O(1-3C alkyl).
 27. The method of claim 26, wherein Y is phenyloptionally substituted with one or more substituents independentlyselected from —F, —Cl, —OMe, —CF₃, —CHF₂, morpholinylethoxy,morpholinylethyl and —OCH₂CH₂OMe.
 28. The method of claim 27, wherein Yis phenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-chloro-5-fluorophenyl,2-methoxyphenyl, 2methoxy-5-fluorophenyl,2-trifluoromethyl-5-fluorophenyl, 2-difluoromethyl-5-fluorophenyl,3-chloro-5-fluorophenyl, 3-fluoro-5-(2-morpholinylethoxyl)phenyl,3-fluoro-5-(2-morpholinylethyl)phenyl,5-fluoro-2-(2-morpholinylethyl)phenyl, 3-fluoro-5-methoxyethoxyphenyl or5-fluoro-2-methoxyethoxyphenyl.
 29. The method of claim 1, wherein Y isfluorophenyl optionally substituted with a substituent selected from—O(1-4C alkyl)hetCyc³, —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6Cdihydroxyalkyl).
 30. The method of claim 29, wherein Y is fluorophenylsubstituted with a substituent selected from morpholinylethoxy,—OCH₂CH₂OMe,2,3-dihydroxypropoxy and 2,2-dimethyl-1,3-dioxolanyl. 31.The method of claim 28, wherein Y is 2,5-difluorophenyl.
 32. The methodof claim 1, wherein Y is a 5-6 membered heteroaryl ring having a ringheteroatom selected from N and S, wherein said ring is optionallysubstituted with one or more substituents independently selected fromhalogen, —O(1-4C alkyl) and (1-4C)alkyl.
 33. The method of claim 32,wherein Y is pyridyl optionally substituted with one or moresubstituents independently selected from F, —OMe, ethyl and Me.
 34. Themethod of claim 33, wherein Y is pyrid-2-yl, pyrid-3-yl,5-fluoropyrid-3-yl, 2-methoxy-5-fluoropyridy-3-yl,2-ethyl-5-fluoropyrid-3-yl or 2-methyl-5-fluoropyridy-3-yl.
 35. Themethod of claim 1, wherein Y is a pyrid-2-on-3-yl ring optionallysubstituted with one or more substituents independently selected formhalogen and (1-4C)alkyl.
 36. The method of claim 35, wherein Y is5-fluoropyridin-2(1H)-one optionally substituted with (1-4C)alkyl. 37.The method of claim 1, wherein: R¹ is H or -(1-6C alkyl); R² is H,-(1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl,-(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO₂NH₂, -(1-6Calkyl)NHSO₂(1-3C alkyl), -(1-6C alkyl)NH₂, -(1-6C alkyl)NH(1-4C alkyl),-(1-6C alkyl)N(1-4C alkyl)₂, -(1-6C alkyl)hetCyc¹, -(1-6C alkyl)hetAr¹,hetAr², hetCyc², —O(1-6C alkyl), —O(3-6C cycloalkyl), or Cyc¹; or NR¹R²forms a 4-6 membered azacyclic ring optionally substituted with one ormore substituents independently selected from -(1-6C)alkyl, —OH, —CO₂Hand -(1-3C alkyl)CO₂H; Cyc¹ is a 3, 4 or 5 membered cycloalkyl ringwhich is optionally substituted with one or more substituentsindependently selected from -(1-4C alkyl), —OH, —OMe, —CO₂H and -(1-4Calkyl)OH; X is CH₂; and Y is (i) fluorophenyl optionally substitutedwith a substituent selected from —O (1-4C alkyl)hetCyc³, -(1-4Calkyl)hetCyc³, —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl),(ii) pyridyl substituted with one or more substituents independentlyselected from F, methyl and ethyl, or (iii) 5-fluoropyridin-2(1H)-oneoptionally substituted with (1-4C)alkyl.
 38. The method of claim 1,wherein R⁴ is OH, F, methyl, or CH₂OH.
 39. The method of claim 38,wherein n is 0, 1 or
 2. 40. The method of claim 1, wherein Y has theabsolute configuration of Figure Ia:


41. The method of claim 1, wherein R³ is H.
 42. The method of claim 1,wherein n is 0-2 and R⁴ is F or Me.
 43. The method of claim 42, whereinn is 0.